Skip to main content
SpringerLink
Log in

The role of brain inflammation and abnormal brain oxygen homeostasis in the development of hepatic encephalopathy

  • Review Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

Abbreviations

AD:

Alzheimer’s disease

ALF:

Acute liver failure

BBB:

Blood-brain barrier

BDL:

Bile-duct ligated

BOLD:

Blood oxygen level-dependent

CBF:

Cerebral blood flow

CLD:

Chronic liver disease

CMRO2 :

Cerebral metabolic rate of oxygen

CNS:

Central nervous system

CD:

Clusters of differentiation

CRP:

C-reactive protein

CX3CL1:

C-X3-C Motif Chemokine Ligand 1

eNOS:

Endothelial nitric oxide synthase

fMR:

Functional magnetic resonance imaging

HE:

Hepatic encephalopathy

Iba1:

Ionized calcium-binding adapter molecule-1

IL:

Interleukin

MCP-1:

Monocyte chemoattractive protein-1

MCT1:

Monocarboxylate transporter-1

mHE:

Minimal hepatic encephalopathy

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

PHES:

Psychometric Hepatic Encephalopathy Score

PET:

Positron emission tomography

TNF:

Tumour necrosis factor

References

  • Allen JS, Tranel D, Bruss J, Damasio H (2006) Correlations between regional brain volumes and memory performance in anoxia. J Clin Exp Neuropsychol 28:457–476

    Article  PubMed  Google Scholar 

  • Anderson CA, Arciniegas DB (2010) Cognitive sequelae of hypoxic-ischemic brain injury: a review. NeuroRehabilitation 26:47–63

    Article  PubMed  Google Scholar 

  • Angelova PR, Kasymov V, Christie I, Sheikhbahaei S, Turovsky E, Marina N, Korsak A, Zwicker J, Teschemacher AG, Ackland GL et al (2015) Functional Oxygen Sensitivity of Astrocytes. J Neurosci 35:10460–10473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Angelova PR, Kerbert AJC, Habtesion A, Hall A, Abramov AY, Jalan R (2022) Hyperammonaemia induces mitochondrial dysfunction and neuronal cell death. JHEP Rep 4:100510

    Article  PubMed  PubMed Central  Google Scholar 

  • Armstead WM (2016) Cerebral Blood Flow Autoregulation and Dysautoregulation. Anesthesiol Clin 34:465–477

    Article  PubMed  PubMed Central  Google Scholar 

  • Balasubramaniyan V, Wright G, Sharma V, Davies NA, Sharifi Y, Habtesion A, Mookerjee RP, Jalan R (2012) Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 302:G145-152

    Article  CAS  PubMed  Google Scholar 

  • Balzano T, Dadsetan S, Forteza J, Cabrera-Pastor A, Taoro-Gonzalez L, Malaguarnera M, Gil-Perotin S, Cubas-Nuñez L, Casanova B, Castro-Quintas A et al (2020) Chronic hyperammonemia induces peripheral inflammation that leads to cognitive impairment in rats: Reversed by anti-TNF-α treatment. J Hepatol 73:582592

    Article  Google Scholar 

  • Balzano T, Forteza J, Borreda I, Molina P, Giner J, Leone P, Urios A, Montoliu C, Felipo V (2018a) Histological Features of Cerebellar Neuropathology in Patients With Alcoholic and Nonalcoholic Steatohepatitis. J Neuropathol Exp Neurol 77:837–845

    Article  CAS  PubMed  Google Scholar 

  • Balzano T, Forteza J, Molina P, Giner J, Monzó A, Sancho-Jiménez J, Urios A, Montoliu C, Felipo V (2018b) The Cerebellum of Patients with Steatohepatitis Shows Lymphocyte Infiltration, Microglial Activation and Loss of Purkinje and Granular Neurons. Sci Rep 8:3004

    Article  PubMed  PubMed Central  Google Scholar 

  • Balzano T, Leone P, Ivaylova G, Castro MC, Reyes L, Ramón C, Malaguarnera M, Llansola M, Felipo V (2021) Rifaximin prevents T-Lymphocytes and macrophages infiltration in cerebellum and restores motor incoordination in rats with mild liver damage. Biomedicines 9:1002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banasiak KJ, Haddad GG (1998) Hypoxia-induced apoptosis: effect of hypoxic severity and role of p53 in neuronal cell death. Brain Res 797:295–304

    Article  CAS  PubMed  Google Scholar 

  • Bao H, Li R, He M, Kang D, Zhao L (2019) DTI Study on Brain Structure and Cognitive Function in Patients with Chronic Mountain Sickness. Sci Rep 9:19334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baune BT, Ponath G, Golledge J, Varga G, Arolt V, Rothermundt M, Berger K (2008) Association between IL-8 cytokine and cognitive performance in an elderly general population–the MEMO-Study. Neurobiol Aging 29:937–944

    Article  CAS  PubMed  Google Scholar 

  • Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17:49–59

    Article  CAS  PubMed  Google Scholar 

  • Bjerring PN, Gluud LL, Larsen FS (2018) Cerebral Blood Flow and Metabolism in Hepatic Encephalopathy-A Meta-Analysis. J Clin Exp Hepatol 8:286–293

    Article  PubMed  PubMed Central  Google Scholar 

  • Bosoi CR, Rose CF (2009) Identifying the direct effects of ammonia on the brain. Metab Brain Dis 24:95–102

    Article  CAS  PubMed  Google Scholar 

  • Bradley TD, Floras JS (2009) Obstructive sleep apnoea and its cardiovascular consequences. Lancet 373:82–93

    Article  PubMed  Google Scholar 

  • Brownlee NNM, Wilson FC, Curran DB, Lyttle N, McCann JP (2020) Neurocognitive outcomes in adults following cerebral hypoxia: A systematic literature review. NeuroRehabilitation 47:83–97

    Article  PubMed  Google Scholar 

  • Burtscher J, Mallet RT, Burtscher M, Millet GP (2021) Hypoxia and brain aging: Neurodegeneration or neuroprotection? Ageing Res Rev 68:101343

    Article  CAS  PubMed  Google Scholar 

  • Butterworth R (2007) Neuronal cell death in hepatic encephalopathy. Metab Brain Dis 22:309–320

    Article  PubMed  Google Scholar 

  • Cagnin A, Taylor-Robinson SD, Forton DM, Banati RB (2006) In vivo imaging of cerebral “peripheral benzodiazepine binding sites” in patients with hepatic encephalopathy. Gut 55:547–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caine D, Watson JD (2000) Neuropsychological and neuropathological sequelae of cerebral anoxia: a critical review. J Int Neuropsychol Soc 6:86–99

    Article  CAS  PubMed  Google Scholar 

  • Catchlove SJ, Macpherson H, Hughes ME, Chen Y, Parrish TB, Pipingas A (2018) An investigation of cerebral oxygen utilization, blood flow and cognition in healthy aging. PLoS One 13:e0197055

    Article  PubMed  PubMed Central  Google Scholar 

  • Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V (2007) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology 46:514–519

    Article  CAS  PubMed  Google Scholar 

  • Celli BR, MacNee W, Force AET (2004) Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23:932–946

    Article  CAS  PubMed  Google Scholar 

  • Chastre A, Bélanger M, Nguyen BN, Butterworth RF (2014) Lipopolysaccharide precipitates hepatic encephalopathy and increases blood-brain barrier permeability in mice with acute liver failure. Liver Int 34:353–361

    Article  CAS  PubMed  Google Scholar 

  • Chastre A, Jiang W, Desjardins P, Butterworth RF (2010) Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure. Metab Brain Dis 25:17–21

    Article  CAS  PubMed  Google Scholar 

  • Clement MA, Bosoi CR, Oliveira MM, Tremblay M, Bemeur C, Rose CF (2021) Bileduct ligation renders the brain susceptible to hypotension-induced neuronal degeneration: Implications of ammonia. J Neurochem 157:561–573

    Article  CAS  PubMed  Google Scholar 

  • Colognesi M, Gabbia D, De Martin S (2020) Depression and cognitive impairment-extrahepatic manifestations of NAFLD and NASH. Biomedicines 8:229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dadsetan S, Balzano T, Forteza J, Agusti A, Cabrera-Pastor A, Taoro-Gonzalez L, Hernandez-Rabaza V, Gomez-Gimenez B, ElMlili N, Llansola M et al (2016a) Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy. J Neuroinflammation 13:245

    Article  PubMed  PubMed Central  Google Scholar 

  • Dadsetan S, Balzano T, Forteza J, Cabrera-Pastor A, Taoro-Gonzalez L, Hernandez-Rabaza V, Gil-Perotín S, Cubas-Núñez L, García-Verdugo JM, Agusti A et al (2016b) Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy. Front Mol Neurosci 9:106

    Article  PubMed  PubMed Central  Google Scholar 

  • Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK, Waagepetersen HS, Schousboe A, Sorensen M (2013) Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake. Hepatology 57:258–265

    Article  CAS  PubMed  Google Scholar 

  • Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dasarathy S, Mookerjee RP, Rackayova V, Rangroo Thrane V, Vairappan B, Ott P, Rose CF (2017) Ammonia toxicity: from head to toe? Metab Brain Dis 32:529–538

    Article  CAS  PubMed  Google Scholar 

  • Dennis CV, Sheahan PJ, Graeber MB, Sheedy DL, Kril JJ, Sutherland GT (2014) Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy. Metab Brain Dis 29:1027–1039

    Article  CAS  PubMed  Google Scholar 

  • Desmond DW, Moroney JT, Sano M, Stern Y (2002) Incidence of dementia after ischemic stroke: results of a longitudinal study. Stroke 33:2254–2260

    Article  PubMed  Google Scholar 

  • Dhanda S, Sandhir R (2018) Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins. Mol Neurobiol 55:3642–3659

    CAS  PubMed  Google Scholar 

  • Disabato DJ, Quan N, Godbout JP (2016) Neuroinflammation: the devil is in the details. J Neurochem 139:136–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duchini A, Govindarajan S, Santucci M, Zampi G, Hofman FM (1996) Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 44:474–482

    CAS  PubMed  Google Scholar 

  • European Association for the Study of the Liver, Electronic address eee, European Association for the Study of the L (2018) EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 69:406-460

  • Felipo V, Urios A, Montesinos E, Molina I, Garcia-Torres ML, Civera M, Olmo JA, Ortega J, Martinez-Valls J, Serra MA et al (2012) Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis 27:51–58

    Article  CAS  PubMed  Google Scholar 

  • Ferdinand P, Roffe C (2016) Hypoxia after stroke: a review of experimental and clinical evidence. Exp Transl Stroke Med 8:9

    Article  PubMed  PubMed Central  Google Scholar 

  • Findley LJ, Barth JT, Powers DC, Wilhoit SC, Boyd DG, Suratt PM (1986) Cognitive impairment in patients with obstructive sleep apnea and associated hypoxemia. Chest 90:686–690

    Article  CAS  PubMed  Google Scholar 

  • França MER, Ramos R, Oliveira WH, Duarte-Silva E, Araújo SMR, Lós DB, Peixoto CA (2019) Tadalafil restores long-term memory and synaptic plasticity in mice with hepatic encephalopathy. Toxicol Appl Pharmacol 379:114673

    Article  PubMed  Google Scholar 

  • Gil E, Kim JM, Jeon K, Park H, Kang D, Cho J, Suh GY, Park J (2018) Recipient Age and Mortality After Liver Transplantation: A Population-based Cohort Study. Transplantation 102:2025–2032

    Article  PubMed  PubMed Central  Google Scholar 

  • Giménez-Garzó C, Fiorillo A, Ballester-Ferre MP, Gallego JJ, Casanova-Ferrer F et al (2021) A New Score Unveils a High Prevalence of Mild Cognitive Impairment in Patients with Nonalcoholic Fatty Liver Disease. J Clin Med 10:2806

    Article  PubMed  PubMed Central  Google Scholar 

  • Gjedde A, Keiding S, Vilstrup H, Iversen P (2010) No oxygen delivery limitation in hepatic encephalopathy. Metab Brain Dis 25:57–63

    Article  CAS  PubMed  Google Scholar 

  • Hadjihambi A (2022) Cerebrovascular alterations in NAFLD: Is it increasing our risk of Alzheimer’s disease? Anal Biochem 636:114387

    Article  CAS  PubMed  Google Scholar 

  • Hadjihambi A, De Chiara F, Hosford PS, Habtetion A, Karagiannis A, Davies N, Gourine AV, Jalan R (2017) Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease. Hepatology 65:1306–1318

    Article  CAS  PubMed  Google Scholar 

  • Hadjihambi A, Cudalbu C, Pierzchala K, Simicic D, Donnelly C, Konstantinou C, Davies N, Habtesion A, Gourine AV, Jalan R et al (2022a) Abnormal brain oxygen homeostasis in an animal model of liver disease. JHEP Rep 4:100509

  • Hadjihambi A, Konstantinou C, Klohs J, Monsorno K, Guennec LA, Donnelly C, Cox J, Hosford SP, Lecca S, Mameli M et al (2022b) Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction. J Hepatol 19:S0168-8278(22)03008-2. Online ahead of print

  • Halder SK, Milner R (2021) Hypoxia in multiple sclerosis; is it the chicken or the egg? Brain 144:402–410

    Article  PubMed  Google Scholar 

  • Hambali A, Kumar J, Hashim NFM, Maniam S, Mehat MZ, Cheema MS, Mustapha M, Adenan MI, Stanslas J, Hamid HA (2021) Hypoxia-Induced Neuroinflammation in Alzheimer’s Disease: Potential Neuroprotective Effects of Centella asiatica. Front Physiol 12:712317

    Article  PubMed  PubMed Central  Google Scholar 

  • Haussinger D, Dhiman RK, Felipo V, Gorg B, Jalan R, Kircheis G, Merli M, Montagnese S, Romero-Gomez M, Schnitzler A, et al (2022) Hepatic encephalopathy. Nat Rev Dis Primers 8:43

  • Häussinger D, Schliess F (2008) Pathogenetic mechanisms of hepatic encephalopathy. Gut 57:1156-1165

  • Hernandez-Rabaza V, Agusti A, Cabrera-Pastor A, Fustero S, Delgado O, TaoroGonzalez L, Montoliu C, Llansola M, Felipo V (2015) Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms. J Neuroinflammation 12:195

    Article  PubMed  PubMed Central  Google Scholar 

  • Hernández-Rabaza V, Cabrera-Pastor A, Taoro-González L, Malaguarnera M, Agustí A, Llansola M, Felipo V (2016) Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane. J Neuroinflammation 13:41

    Article  PubMed  PubMed Central  Google Scholar 

  • Hirota K (2015) Involvement of hypoxia-inducible factors in the dysregulation of oxygen homeostasis in sepsis. Cardiovasc Hematol Disord Drug Targets 15:29–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosford PS, Gourine AV (2019) What is the key mediator of the neurovascular coupling response? Neurosci Biobehav Rev 96:174–181

    Article  PubMed  PubMed Central  Google Scholar 

  • Iadecola C (2017) The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96:17–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iversen P, Mouridsen K, Hansen MB, Jensen SB, Sorensen M, Bak LK, Waagepetersen HS, Schousboe A, Ott P, Vilstrup H et al (2014) Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [(11)C]acetate in humans. Front Neurosci 8:353

    Article  PubMed  PubMed Central  Google Scholar 

  • Iversen P, Sorensen M, Bak LK, Waagepetersen HS, Vafaee MS, Borghammer P, Mouridsen K, Jensen SB, Vilstrup H, Schousboe A et al (2009) Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology 136:863–871

    Article  PubMed  Google Scholar 

  • Jaeger V, DeMorrow S, McMillin M (2019) The direct contribution of astrocytes and microglia to the pathogenesis of hepatic encephalopathy. J Clin Transl Hepatol 7:352–361

  • Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, Stadlbauer V, Gustot T, Bernardi M, Canton R et al (2014) Bacterial infections in cirrhosis: A position statement based on the EASL Special Conference 2013. J Hepatol 60:1310–1324

    Article  PubMed  Google Scholar 

  • Jalan R, Rose CF (2022) Heretical thoughts into hepatic encephalopathy. J Hepatol 77:539–548

    Article  PubMed  Google Scholar 

  • Jiyeon O, C. H-J, H. SH, K. IK, S. K (2005) Hypoxia as an Initiator of Neuroinflammation: Microglial Connections. Curr Neuropharmacol 3:183-191

  • Khot S, Tirschwell DL (2006) Long-term neurological complications after hypoxicischemic encephalopathy. Semin Neurol 26:422–431

    Article  PubMed  Google Scholar 

  • Kjærgaard K, Mikkelsen ACD, Wernberg CW, Grønkjær LL, Eriksen PL, Damholdt MF, Mookerjee RP, Vilstrup H, Lauridsen MM, Thomsen KL (2021) Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease—Current Knowledge, Mechanisms and Perspectives. J Clin Med 10:673

    Article  PubMed  PubMed Central  Google Scholar 

  • Kokmen E, Whisnant JP, O’Fallon WM, Chu CP, Beard CM (1996) Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960–1984). Neurology 46:154–159

    Article  CAS  PubMed  Google Scholar 

  • Kong L, Wang Z, Liang X, Wang Y, Gao L, Ma C (2019) Monocarboxylate transporter 1 promotes classical microglial activation and pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3. J Neuroinflammation 16:240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lall R, Mohammed R, Ojha U (2019) What are the links between hypoxia and Alzheimer’s disease? Neuropsychiatr Dis Treat 15:1343–1354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lawley JS, Macdonald JH, Oliver SJ, Mullins PG (2017) Unexpected reductions in regional cerebral perfusion during prolonged hypoxia. J Physiol 595:935–947

    Article  CAS  PubMed  Google Scholar 

  • Leone P, Mincheva G, Balzano T, Malaguarnera M, Felipo V, Llansola M (2022) Rifaximin improves spatial learning and memory impairment in rats with liver damage-associated neuroinflammation. Biomedicines 10:1263

  • Lopez-Valdes HE, Martinez-Coria H (2016) The Role of Neuroinflammation in Age-Related Dementias. Rev Invest Clin 68:40–48

    CAS  PubMed  Google Scholar 

  • Lourenco CF, Ledo A, Dias C, Barbosa RM, Laranjinha J (2015) Neurovascular and neurometabolic derailment in aging and Alzheimer’s disease. Front Aging Neurosci 7:103

    PubMed  PubMed Central  Google Scholar 

  • Malpetti M, Kievit RA, Passamonti L, Jones PS, Tsvetanov KA, Rittman T, Mak E, Nicastro N, Bevan-Jones WR, Su L et al (2020) Microglial activation and tau burden predict cognitive decline in Alzheimer’s disease. Brain 143:1588–1602

    Article  PubMed  PubMed Central  Google Scholar 

  • Mangas-Losada A, García-García R, Urios A, Escudero-García D, Tosca J, Giner-Durán R, Serra MA, Montoliu C, Felipo V (2017) Minimal hepatic encephalopathy is associated with expansion and activation of CD4+CD28−, Th22 and Tfh and B lymphocytes. Sci Rep 7:6683

    Article  PubMed  PubMed Central  Google Scholar 

  • McNicholas WT (2009) Chronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular disease. Am J Respir Crit Care Med 180:692–700

    Article  CAS  PubMed  Google Scholar 

  • Mikkelsen ACD, Kjærgaard K, Mookerjee RP, Vilstrup H, Wegener G, Bay-Richter C, Thomsen KL (2022) Non-alcoholic fatty liver disease: also a disease of the brain? A systematic review of the preclinical evidence. Neurochem Res. Online ahead of print

  • Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD et al (1998) Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 351:857–861

    Article  CAS  PubMed  Google Scholar 

  • Montoliu C, Piedrafita B, Serra MA, del Olmo JA, Urios A, Rodrigo JM, Felipo V (2009) IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy. J Clin Gastroenterol 43:272–279

    Article  CAS  PubMed  Google Scholar 

  • Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, Gustot T, Saliba F, Domenicali M, et al (2013) Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 144:1426–1437, 1437 e1421–1429

  • Moreira TJ, Pierre K, Maekawa F, Repond C, Cebere A, Liljequist S, Pellerin L (2009) Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells. J Cereb Blood Flow Metab 29:1273–1283

    Article  CAS  PubMed  Google Scholar 

  • Nakata H, Miyamoto T, Ogoh S, Kakigi R, Shibasaki M (2017) Effects of acute hypoxia on human cognitive processing: a study using ERPs and SEPs. J Appl Physiol 123:1246–1255

  • Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, Kyrargyri V, Pfeiffer T, Khennouf L, Madry C et al (2019) Amyloid beta oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes. Science 365:250

  • Ock J, Cho H, Hong HS, Kim KI, Suk K (2005) Hypoxia as an Initiator of Neuroinflammation: Microglial Connections. Curr Neuropharmacol 3:183–191

    Article  CAS  Google Scholar 

  • Ostergaard L, Engedal TS, Aamand R, Mikkelsen R, Iversen NK, Anzabi M, NaessSchmidt ET, Drasbek KR, Bay V, Blicher JU et al (2014) Capillary transit time heterogeneity and flow-metabolism coupling after traumatic brain injury. J Cereb Blood Flow Metab 34:1585–1598

    Article  PubMed  PubMed Central  Google Scholar 

  • Park J, Jung S, Kim SM, Park IY, Bui NA, Hwang GS, Han IO (2021) Repeated hypoxia exposure induces cognitive dysfunction, brain inflammation, and amyloidbeta/p-Tau accumulation through reduced brain O-GlcNAcylation in zebrafish. J Cereb Blood Flow Metab 41:3111–3126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peers C, Dallas ML, Boycott HE, Scragg JL, Pearson HA, Boyle JP (2009) Hypoxia and neurodegeneration. Ann N Y Acad Sci 1177:169–177

    Article  CAS  PubMed  Google Scholar 

  • Pellerin L, Pellegri G, Martin JL, Magistretti PJ (1998) Expression of monocarboxylate transporter mRNAs in mouse brain: support for a distinct role of lactate as an energy substrate for the neonatal vs. adult brain. Proc Natl Acad Sci U S A 95:3990–3995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perry VH (2004) The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 18:407–413

    Article  CAS  PubMed  Google Scholar 

  • Raichle ME (1983) The pathophysiology of brain ischemia. Ann Neurol 13:2–10

    Article  CAS  PubMed  Google Scholar 

  • Ramos-Vega M, Kjellman P, Todorov MI, Kylkilahti TM, Backstrom BT, Erturk A, Madsen CD, Lundgaard I (2022) Mapping of neuroinflammation-induced hypoxia in the spinal cord using optoacoustic imaging. Acta Neuropathol Commun 10:51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rivera DS, Lindsay CB, Codocedo JF, Carreño LE, Cabrera D, Arrese MA, Vio CP, Bozinovic F, Inestrosa NC (2018) Long-Term, Fructose-Induced Metabolic Syndrome-Like Condition Is Associated with Higher Metabolism, Reduced Synaptic Plasticity and Cognitive Impairment in Octodon degus. Mol Neurobiol 55:9169–9187

    Article  CAS  PubMed  Google Scholar 

  • Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, GarciaVerdugo JM, Felipo V (2010) Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139:675–684

    Article  CAS  PubMed  Google Scholar 

  • Rose CF, Amodio P, Bajaj JS, Dhiman RK, Montagnese S, Taylor-Robinson SD, Vilstrup H, Jalan R (2020) Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J Hepatol 73:1526–1547

    Article  PubMed  Google Scholar 

  • Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW (2001) Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 32:2575–2579

    Article  CAS  PubMed  Google Scholar 

  • Safavynia SA, Goldstein PA (2018) The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment. Front Psychiatry 9:752

    Article  PubMed  Google Scholar 

  • Schaefer A, Journaux M, Mourabit HE, Mouri S, Wendum D, Lasnier E, Couraud PO, Housset C, Thabut D, Rudler M et al (2022) A systemic mechanism of increased transendothelial migration of leukocytes through the blood-brain barrier in hepatic encephalopathy. Clin Res Hepatol Gastroenterol 46:101801

    Article  CAS  PubMed  Google Scholar 

  • Schultz IZ, Sepehry AA, Greer SC (2018) Anoxia-Hypoxia in Forensic Neuropsychological Assessment: Cognitive Impact of Pulmonary Injuries, Respiratory Distress, Cerebral Blood Hypoperfusion and Major Surgeries. Psychol Injury Law 11:153–170

    Article  Google Scholar 

  • Sharp FR, Bernaudin M (2004) HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5:437–448

    Article  CAS  PubMed  Google Scholar 

  • Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254

    Article  CAS  PubMed  Google Scholar 

  • Shawcross DL, Wright G, Olde Damink SW, Jalan R (2007) Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 22:125–138

    Article  CAS  PubMed  Google Scholar 

  • Snyder B, Simone SM, Giovannetti T, Floyd TF (2021) Cerebral Hypoxia: Its Role in Age-Related Chronic and Acute Cognitive Dysfunction. Anesth Analg 132:1502–1513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sochocka M, Diniz BS, Leszek J (2017) Inflammatory Response in the CNS: Friend or Foe? Mol Neurobiol 54:8071–8089

    Article  CAS  PubMed  Google Scholar 

  • Soffer D, Sherman Y, Tur-Kaspa R, Eid A (1995) Acquired hepatocerebral degeneration in a liver transplant recipient. Acta Neuropathol 90:107–111

    Article  CAS  PubMed  Google Scholar 

  • Sørensen M, Walls AB, Bak LK, Andersen JV, Ott P, Vilstrup H, Schousboe A (2022) Low cerebral energy metabolism in hepatic encephalopathy reflects low neuronal energy demand. Role of ammonia-induced increased GABAergic tone. Anal Biochem 654:114766

  • Stadlbauer V, Wright GA, Banaji M, Mukhopadhya A, Mookerjee RP, Moore K, Jalan R (2008) Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology 134:111–119

    Article  PubMed  Google Scholar 

  • Strauss GI, Hansen BA, Herzog T, Larsen FS (2000) Cerebral autoregulation in patients with end-stage liver disease. Eur J Gastroenterol Hepatol 12:767–771

    Article  CAS  PubMed  Google Scholar 

  • Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, Goodman SN (2004) Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology 23:159–169

    Article  PubMed  Google Scholar 

  • Tatemichi TK, Paik M, Bagiella E, Desmond DW, Stern Y, Sano M, Hauser WA, Mayeux R (1994) Risk of dementia after stroke in a hospitalized cohort: results of a longitudinal study. Neurology 44:1885–1891

    Article  CAS  PubMed  Google Scholar 

  • Teunissen CE, van Boxtel MP, Bosma H, Bosmans E, Delanghe J, De Bruijn C, Wauters A, Maes M, Jolles J, Steinbusch HW et al (2003) Inflammation markers in relation to cognition in a healthy aging population. J Neuroimmunol 134:142–150

    Article  CAS  PubMed  Google Scholar 

  • Tobin MJ, Laghi F, Jubran A (2020) Why COVID-19 Silent Hypoxemia Is Baffling to Physicians. Am J Respir Crit Care Med 202:356–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tondo G, Boccalini C, Caminiti SP, Presotto L, Filippi M, Magnani G, Frisoni GB, Iannaccone S, Perani D (2021) Brain Metabolism and Microglia Activation in Mild Cognitive Impairment: A Combined [18F]FDG and [11C]-(R)-PK11195 PET Study. J Alzheimers Dis 80:433–445

    Article  CAS  PubMed  Google Scholar 

  • Tranah TH, Ballester MP, Carbonell-Asins JA, Ampuero J, Alexandrino G, Caracostea A, Sanchez-Torrijos Y, Thomsen KL, Kerbert AJC, Capilla-Lozano M et al (2022) Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis. J Hepatol S0168-8278(22)02947-6. Online ahead of print

  • Veniaminova E, Oplatchikova M, Bettendorff L, Kotenkova E, Lysko A, Vasilevskaya E, Kalueff AV, Fedulova L, Umriukhin A, Lesch KP et al (2020) Prefrontal cortex inflammation and liver pathologies accompany cognitive and motor deficits following Western diet consumption in non-obese female mice. Life Sci 241:117163

    Article  CAS  PubMed  Google Scholar 

  • Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P (2014) Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 60:715–735

    Article  PubMed  Google Scholar 

  • Wang Q, Chen G, Schindler SE, Christensen J, McKay NS, Liu J, Wang S, Sun Z, Hassenstab J, Su Y et al (2022a) Baseline microglial activation correlates with brain amyloidosis and longitudinal cognitive decline in alzheimer disease. Neurol Neuroimmunol Neuroinflamm 9(3):e1152

  • Wang X, Cui L, Ji X (2022b) Cognitive impairment caused by hypoxia: from clinical evidences to molecular mechanisms. Metab Brain Dis 37:51–66

    Article  CAS  PubMed  Google Scholar 

  • Weiss HJ, Angiari S (2020) Metabolite transporters as regulators of immunity. Metabolites 10:418

  • Weiss N, Dam G, Rose CF (2018) Ammonia: This is not the end but rather the end of the beginning. J Hepatol 68:1110–1113

    Article  PubMed  Google Scholar 

  • Willie CK, Tzeng YC, Fisher JA, Ainslie PN (2014) Integrative regulation of human brain blood flow. J Physiol 592:841–859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson M, Staniforth A, Till R, das Nair R, Vesey P (2014) The psychosocial outcomes of anoxic brain injury following cardiac arrest. Resuscitation 85:795-800

  • Xie JC, Ma XY, Liu XH, Yu J, Zhao YC, Tan Y, Liu XY, Zhao YX (2018) Hypoxia increases amyloid-beta level in exosomes by enhancing the interaction between CD147 and Hook1. Am J Transl Res 10:150–163

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yaffe K, Lindquist K, Penninx BW, Simonsick EM, Pahor M, Kritchevsky S, Launer L, Kuller L, Rubin S, Harris T (2003) Inflammatory markers and cognition in wellfunctioning African-American and white elders. Neurology 61:76–80

    Article  CAS  PubMed  Google Scholar 

  • Zander R, Vaupel P (1985) Proposal for using a standardized terminology on oxygen transport to tissue. Adv Exp Med Biol 191:965–970

    Article  CAS  PubMed  Google Scholar 

  • Zemtsova I, Görg B, Keitel V, Bidmon HJ, Schrör K, Häussinger D (2011) Microglia activation in hepatic encephalopathy in rats and humans. Hepatology 54:204–215

    Article  CAS  PubMed  Google Scholar 

  • Zhang LJ, Yang G, Yin J, Liu Y, Qi J (2007) Neural mechanism of cognitive control impairment in patients with hepatic cirrhosis: a functional magnetic resonance imaging study. Acta Radiol 48:577–587

    Article  CAS  PubMed  Google Scholar 

  • Zheng G, Lu H, Yu W, Luo S, Liu Y, Liu W, Liu H, Wu L, Zheng L, Kong X et al (2017) Severity-specific alterations in CBF, OEF and CMRO2 in cirrhotic patients with hepatic encephalopathy. Eur Radiol 27:4699–4709

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Figure 

Fig. 1
figure 1

Schematic diagram summarising the contribution and interplay of brain inflammation and abnormal oxygen homeostasis in the development of hepatic encephalopathy in chronic liver disease

Full size image

1 was created with BioRender.com.

Funding

This research was generously supported by grants from The Foundation of Manufacturer Vilhelm Pedersen and Wife, and Novo Nordisk Foundation (NNF19OC0055039).

Author information

Authors and Affiliations

  1. Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    Anne Catrine Daugaard Mikkelsen, Karen Louise Thomsen & Rajeshwar Prosad Mookerjee

  2. UCL Institute of Liver and Digestive Health, University College London, London, UK

    Karen Louise Thomsen & Rajeshwar Prosad Mookerjee

  3. The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, SE5 9NT, UK

    Anna Hadjihambi

  4. Faculty of Life Sciences and Medicine, King’s College London, London, UK

    Anna Hadjihambi

Authors
  1. Anne Catrine Daugaard Mikkelsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen Louise Thomsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rajeshwar Prosad Mookerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Hadjihambi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AH designed and led the review; AH and ACDM wrote the review and created the figure; RPM and KLT contributed to the clinical aspects and critically reviewed the manuscript.

Corresponding authors

Correspondence to Anne Catrine Daugaard Mikkelsen or Anna Hadjihambi.

Ethics declarations

Conflicts of interest/Competing interests

Raj Mookerjee has research collaborations with Yaqrit Ltd and CyberLiver Ltd. The other authors have nothing to disclose.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mikkelsen, A.C.D., Thomsen, K.L., Mookerjee, R.P. et al. The role of brain inflammation and abnormal brain oxygen homeostasis in the development of hepatic encephalopathy. Metab Brain Dis 38, 1707–1716 (2023). https://doi.org/10.1007/s11011-022-01105-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-022-01105-2

Keywords

Search

Navigation