Skip to main content
SpringerLink
Log in

Hepatic Encephalopathy: A Primary Neurogliopathy

  • Chapter
  • First Online:
Book cover Pathological Potential of Neuroglia

  • 859 Accesses

Abstract

Hepatic encephalopathy (HE) and brain edema are serious central nervous complications of both acute and chronic liver failure. HE starts as a neuropsychiatric syndrome beginning with changes in personality and sleep disturbances progressing through cognitive dysfunction and motor symptoms to stupor and coma. In acute liver failure (ALF) progression may be very rapid, sometimes of the order of days (Butterworth and Vaquero, The liver; biology and pathobiology, pp. 600–617, 2009). Since the appearance of overt signs of encephalopathy in liver failure generally heralds a poor prognosis with a significant impact on clinical management options, on liver transplant outcome and on health-related quality of life, rational effective therapies are urgently required. Such therapies require knowledge of the precise mechanisms implicated in the pathogenesis of HE.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agusti A, Cauli O, Rodrigo R, Llansola M, Hernandez-Rabaza V, Felipo V (2011) p38 MAP kinase is a therapeutic target for hepatic encephalopathy in rats with portacaval shunts. Gut 60:1572–1579

    Article  PubMed  CAS  Google Scholar 

  • Ahboucha S, Butterworth RF (2005) Role of endogenous benzodiazepine ligands and their GABA-A-associated receptors in hepatic encephalopathy. Metab Brain Dis 20:425–437

    Article  PubMed  CAS  Google Scholar 

  • Ahboucha S, Butterworth RF (2008) The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy. Neurochem Int 52:575–587

    Article  PubMed  CAS  Google Scholar 

  • Alvarez VM, Rama Rao KV, Brahmbhatt M, Norenberg MD (2011) Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. J Neurosci Res 89:2028–2040

    Article  PubMed  CAS  Google Scholar 

  • Belanger M, Desjardins P, Chatauret N, Butterworth RF (2002) Loss of expression of glial fibrillary acidic protein in acute hyperammonemia. Neurochem Int 41:155–160

    Article  PubMed  CAS  Google Scholar 

  • Belanger M, Desjardins P, Chatauret N, Butterworth RF (2006) Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure. Glia 53:557–562

    Article  PubMed  Google Scholar 

  • Bemeur C, Chastre A, Desjardins P, Butterworth R (2010a) No changes in expression of tight junction proteins or blood-brain barrier permeability in azoxymethane-induced experimental acute liver failure. Neurochem Int 56:205–207

    Article  CAS  Google Scholar 

  • Bemeur C, Qu H, Desjardins P, Butterworth RF (2010b) IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. Neurochem Int 56:213–215

    Article  CAS  Google Scholar 

  • Bernal W, Donaldson P, Underhill J, Wendon J, Williams R (1998) Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. J Hepatol 29:53–59

    Article  PubMed  CAS  Google Scholar 

  • Bradley M, McMillin M, Galindo C, Frampton G, Pae H, Quinn M, DeMorrow S (2013) CCR2 and CCR4 activation via CCL2/MCP-1 contributes to neurological decline and microglia activation associated with hepatic encephalopathy pathogenesis. Gastroenterology 144:S1026–S1027

    Google Scholar 

  • Brusilow SW, Koehler RC, Traystman RJ, Cooper AJ (2010) Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics 7:452–470

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Butterworth RF (2011) Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology 53:1372–1376

    Article  PubMed  Google Scholar 

  • Butterworth RF (2013a) The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol 10:522–528

    Article  CAS  Google Scholar 

  • Butterworth RF (2013b) Parkinsonism in cirrhosis: pathogenesis and current therapeutic options. Metab Brain Dis 28:261–267

    Article  CAS  Google Scholar 

  • Butterworth RF, Vaquero J (2009) Hepatic encephalopathy. In: Arias I, Alter H, Boyer J, Cohen D, Fausto N, Shafritz D et al (eds) The liver; biology and pathobiology. Wiley, Chichester, pp 600–617

    Google Scholar 

  • Butterworth RF, Norenberg MD, Felipo V, Ferenci P, Albrecht J, Blei AT (2009) Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 29:783–788

    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  PubMed  CAS  PubMed Central  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  PubMed  CAS  Google Scholar 

  • Chastre A, Belanger M, Beauchesne E, Nguyen BN, Desjardins P, Butterworth RF (2012) Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications. PloS ONE 7:e49670

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Gastroenterology 125:815–824

    Article  PubMed  CAS  Google Scholar 

  • Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653

    Article  PubMed  CAS  Google Scholar 

  • Conductier G, Blondeau N, Guyon A, Nahon JL, Rovere C (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 224:93–100

    Article  PubMed  CAS  Google Scholar 

  • Cubelos B, Gonzalez-Gonzalez IM, Gimenez C, Zafra F (2005) Amino acid transporter SNAT5 localizes to glial cells in the rat brain. Glia 49:230–244

    Article  PubMed  Google Scholar 

  • D’Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci 29:2089–2102

    Article  PubMed  Google Scholar 

  • Deng YY, Lu J, Ling EA, Kaur C (2011) Role of microglia in the process of inflammation in the hypoxic developing brain. Front Biosci (Schol Ed) 3:884–900

    Article  Google Scholar 

  • Desjardins P, Du T, Jiang W, Peng L, Butterworth RF (2012) Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem Int 60:690–696

    Article  PubMed  CAS  Google Scholar 

  • Eefsen M, Jelnes P, Schmidt LE, Vainer B, Bisgaard HC, Larsen FS (2010) Brain expression of the water channels aquaporin-1 and -4 in mice with acute liver injury, hyperammonemia and brain edema. Metab Brain Dis 25:315–323

    Article  PubMed  CAS  Google Scholar 

  • Felipo V, Minana MD, Grisolia S (1988) Long-term ingestion of ammonium increases acetylglutamate and urea levels without affecting the amount of carbamoyl-phosphate synthase. Eur J Biochem/FEBS 176:567–571

    Article  CAS  Google Scholar 

  • Gorg B, Bidmon HJ, Haussinger D (2013) Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy. Hepatology 57:2436–2447

    Article  PubMed  Google Scholar 

  • Jiang W, Qu H, Desjardins P, Chatauret N, Belanger M, Butterworth R (2006) Unequivocal evidence for cytokine accumulation in brain in experimental acute liver failure. Hepatology 44:336A

    Google Scholar 

  • Jiang W, Desjardins P, Butterworth RF (2009a) Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem 109:485–493

    Article  CAS  Google Scholar 

  • Jiang W, Desjardins P, Butterworth RF (2009b) Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab 29:944–952

    Article  CAS  Google Scholar 

  • Kato M, Hughes RD, Keays RT, Williams R (1992) Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 15:1060–1066

    Article  PubMed  CAS  Google Scholar 

  • Kerfoot SM, D’Mello C, Nguyen H, Ajuebor MN, Kubes P, Le T, Swain MG (2006) TNF-alpha-secreting monocytes are recruited into the brain of cholestatic mice. Hepatology 43:154–162

    Article  PubMed  Google Scholar 

  • Kim SE, Lee EO, Yang JH, Kang JH, Suh YH, Chong YH (2012) 15-deoxy-Delta(1)(2),(1)(4) -prostaglandin J(2) inhibits human immunodeficiency virus-1 tat-induced monocyte chemoattractant protein-1/CCL2 production by blocking the extracellular signal-regulated kinase-1/2 signaling pathway independently of peroxisome proliferator-activated receptor-gamma and heme oxygenase-1 in rat hippocampal slices. J Neurosci Res 90:1732–1742

    Article  PubMed  CAS  Google Scholar 

  • Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF (1997) Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett 229:201–203

    Article  PubMed  CAS  Google Scholar 

  • Kril JJ, Flowers D, Butterworth RF (1997) Distinctive pattern of Bergmann glial pathology in human hepatic encephalopathy. Mol chem neuropathol 31:279–287

    Article  PubMed  CAS  Google Scholar 

  • Lachmann V, Gorg B, Bidmon HJ, Keitel V, Haussinger D (2013) Precipitants of hepatic encephalopathy induce rapid astrocyte swelling in an oxidative stress dependent manner. Arch Biochem Biophys 536:143–151

    Article  PubMed  CAS  Google Scholar 

  • Lambertsen KL, Biber K, Finsen B (2012) Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab 32:1677–1698

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Laubenberger J, Haussinger D, Bayer S, Gufler H, Hennig J, Langer M (1997) Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology 112:1610–1616

    Article  PubMed  CAS  Google Scholar 

  • McMillin M, Galindo C, Frampton G, Pae H, Quinn M, DeMorrow S (2012a) Gli1 is activated via the non-classical TGFβ/SMAD3 pathway rather than the sonic hedgehog pathway in a murine model of hepatic encephalopathy. FASEB J 26:1110–1112

    Article  Google Scholar 

  • McMillin M, Galindo C, Frampton G, Pae H, Quinn M, Bradley M, Jacobs A, DeMorrow S (2012b) Increased neuronal chemokine CCL2/MCP-1 expression is associated with hepatic encephalopathy and contributes to neurological decline. Hepatology 56:958A

    Google Scholar 

  • McMillin M, Galindo C, Frampton G, Pae H, Quinn M, DeMorrow S (2013) CCL3 is upregulated in the frontal cortex during hepatic encephalopathy and can be inhibited by the suppression of circulating TGFβ1. J Neurochem 125(Suppl S1):136

    Google Scholar 

  • Neary JT, Whittemore SR, Zhu Q, Norenberg MD (1994) Destabilization of glial fibrillary acidic protein mRNA in astrocytes by ammonia and protection by extracellular ATP. J Neurochem 63:2021–2027

    Article  PubMed  CAS  Google Scholar 

  • Nguyen JH (2010) Subtle BBB alterations in brain edema associated with acute liver failure. Neurochem Int 56:203–204; author reply 205–207

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Norenberg MD (1987) The role of astrocytes in hepatic encephalopathy. Neurochem Pathol 6:13–33

    Article  PubMed  CAS  Google Scholar 

  • Obara-Michlewska M, Pannicke T, Karl A, Bringmann A, Reichenbach A, Szeliga M, Hilgier W, Wrzosek A, Szewczyk A, Albrecht J (2011) Down-regulation of Kir4.1 in the cerebral cortex of rats with liver failure and in cultured astrocytes treated with glutamine: implications for astrocytic dysfunction in hepatic encephalopathy. J Neurosci Res 89:2018–2027

    Article  PubMed  CAS  Google Scholar 

  • Odeh M (2007) Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory. Eur J Clin Invest 37:291–304

    Article  PubMed  CAS  Google Scholar 

  • Rama Rao KV, Chen M, Simard JM, Norenberg MD (2003) Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport 14:2379–2382

    Article  PubMed  CAS  Google Scholar 

  • Rangroo Thrane V, Thrane AS, Chang J, Alleluia V, Nagelhus EA, Nedergaard M (2012) Real-time analysis of microglial activation and motility in hepatic and hyperammonemic encephalopathy. Neuroscience 220:247–255

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012:756357

    Article  PubMed  PubMed Central  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  PubMed  CAS  Google Scholar 

  • Sobel RA, DeArmond SJ, Forno LS, Eng LF (1981) Glial fibrillary acidic protein in hepatic encephalopathy. An immunohistochemical study. J Neuropathol Exp Neurol 40:625–632

    Article  PubMed  CAS  Google Scholar 

  • Suarez I, Bodega G, Fernandez B (2000) Modulation of glutamate transporters (GLAST, GLT-1 and EAAC1) in the rat cerebellum following portocaval anastomosis. Brain Res 859:293–302

    Article  PubMed  CAS  Google Scholar 

  • Vaquero J, Butterworth RF (2006) The brain glutamate system in liver failure. J Neurochem 98:661–669

    Article  PubMed  CAS  Google Scholar 

  • Villano G, Lunardi F, Turato C, Schiff S, Tono N, Campagna F, Gatta A, Amodio P, Calabrese F, Pontissa P (2012) Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure. Exp Biol Med 237:1474–1482

    Article  CAS  Google Scholar 

  • Wright G, Shawcross D, Olde Damink SW, Jalan R (2007) Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 22:375–388

    Article  PubMed  CAS  Google Scholar 

  • Wright G, Soper R, Brooks HF, Stadlbauer V, Vairappan B, Davies NA, Andreola F, Hodges S, Moss RF, Davies DC, Jalan R (2010) Role of aquaporin-4 in the development of brain oedema in liver failure. J Hepatol 53:91–97

    Article  PubMed  CAS  Google Scholar 

  • Yao HL, Gao FH, Li ZZ, Wu HX, Xu MD, Zhang Z, Dai QY (2012) Monocyte chemoattractant protein-1 mediates angiotensin II-induced vascular smooth muscle cell proliferation via SAPK/JNK and ERK1/2. Mol Cell Biochem 366:355–362

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Zwingmann C, Desjardins P, Hazell A, Chatauret N, Michalak A, Butterworth RF (2002) Reduced expression of astrocytic glycine transporter (Glyt-1) in acute liver failure. Metab Brain Dis 17:263–273

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This material is the result of work supported in part with resources and the use of facilities at the Central Texas Veterans Health Care System, Temple, Texas and from The Canadian Institutes of Health Research (CIHR).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, 1901 South 1st Street, 76504, Temple, TX, USA

    Sharon DeMorrow

  2. Neuroscience Research Unit, Hopital St-Luc (CHUM), 1058 St-Denis, H2X 3J4, Montreal, QC, Canada

    Roger F Butterworth

Authors
  1. Sharon DeMorrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger F Butterworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger F Butterworth .

Editor information

Editors and Affiliations

  1. Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Vladimir Parpura

  2. Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom

    Alexei Verkhratsky

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

DeMorrow, S., Butterworth, R. (2014). Hepatic Encephalopathy: A Primary Neurogliopathy. In: Parpura, V., Verkhratsky, A. (eds) Pathological Potential of Neuroglia. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0974-2_15

Download citation

Publish with us

Policies and ethics

Search

Navigation