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Hepatic encephalopathy: Pathogenesis

Peter Ferenci, MD
Section Editor
Bruce A Runyon, MD
Deputy Editor
Kristen M Robson, MD, MBA, FACG


Hepatic encephalopathy (HE) or portosystemic encephalopathy (PSE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver failure (see "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis").

However, HE is not a single clinical entity. It may reflect either a reversible metabolic encephalopathy, brain atrophy, brain edema, or any combination of these conditions. The mechanisms causing brain dysfunction in liver failure are still unknown. In advanced coma, the effects of brain swelling, impaired cerebral perfusion, and reversible impairment of neurotransmitter systems cannot be distinguished. Furthermore, these events overlap, at least in models of acute liver failure.

Data on cerebral function in HE are usually derived from animal studies since brains of patients with HE cannot be studied with neurochemical or neurophysiologic methods. It is beyond the scope of this review to discuss each of the animal models in detail, but it must be appreciated that they may not accurately reflect human disease.

The metabolic factors that contribute to the development of HE will be reviewed here [1]. Ammonia is clearly implicated; in addition, there may be a role for inhibitory neurotransmission through gamma-aminobutyric acid (GABA) receptors in the central nervous system and changes in central neurotransmitters and circulating amino acids. These hypotheses are not mutually exclusive, and multiple factors may be present at the same time. Therapies for hepatic encephalopathy are based upon these hypotheses. (See "Hepatic encephalopathy in adults: Treatment".)

Some precipitating factors are directly related to liver failure (eg, decreased metabolism of ammonia). Concurrent disorders can also contribute to the development of HE. These factors include (table 1):

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Literature review current through: Nov 2017. | This topic last updated: Dec 11, 2017.
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  1. Ferenci P. Brain dysfunction in fulminant hepatic failure. J Hepatol 1994; 21:487.
  2. Saija A, Princi P, Lanza M, et al. Systemic cytokine administration can affect blood-brain barrier permeability in the rat. Life Sci 1995; 56:775.
  3. Cauli O, Rodrigo R, Piedrafita B, et al. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology 2007; 46:514.
  4. O'Beirne JP, Chouhan M, Hughes RD. The role of infection and inflammation in the pathogenesis of hepatic encephalopathy and cerebral edema in acute liver failure. Nat Clin Pract Gastroenterol Hepatol 2006; 3:118.
  5. Strauss G, Hansen BA, Kirkegaard P, et al. Liver function, cerebral blood flow autoregulation, and hepatic encephalopathy in fulminant hepatic failure. Hepatology 1997; 25:837.
  6. Larsen FS, Knudsen GM, Hansen BA. Pathophysiological changes in cerebral circulation, oxidative metabolism and blood-brain barrier in patients with acute liver failure. Tailored cerebral oxygen utilization. J Hepatol 1997; 27:231.
  7. Artz SA, Paes IC, Faloon WW. Hypokalemia-induced hepatic coma in cirrhosis. Occurrence despite neomycin therapy. Gastroenterology 1966; 51:1046.
  8. Gabduzda GJ, Hall PW 3rd. Relation of potassium depletion to renal ammonium metabolism and hepatic coma. Medicine (Baltimore) 1966; 45:481.
  9. Suto H, Azuma T, Ito S, et al. Helicobacter pylori infection induces hyperammonaemia in Mongolian gerbils with liver cirrhosis. Gut 2001; 48:605.
  10. Blei AT. Helicobacter pylori, harmful to the brain? Gut 2001; 48:590.
  11. Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 2006; 44:788.
  12. Sawhney R, Jalan R. Liver: the gut is a key target of therapy in hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 2015; 12:7.
  13. Zieve L, Doizaki WM, Zieve J. Synergism between mercaptans and ammonia or fatty acids in the production of coma: a possible role for mercaptans in the pathogenesis of hepatic coma. J Lab Clin Med 1974; 83:16.
  14. Weissenborn K, Ahl B, Fischer-Wasels D, et al. Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy. Gut 2007; 56:1736.
  15. Aldridge DR, Tranah EJ, Shawcross DL. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol 2015; 5:S7.
  16. Grippon P, Le Poncin Lafitte M, Boschat M, et al. Evidence for the role of ammonia in the intracerebral transfer and metabolism of tryptophan. Hepatology 1986; 6:682.
  17. James JH, Ziparo V, Jeppsson B, Fischer JE. Hyperammonaemia, plasma aminoacid imbalance, and blood-brain aminoacid transport: a unified theory of portal-systemic encephalopathy. Lancet 1979; 2:772.
  18. Cordoba J, Blei AT. Brain edema and hepatic encephalopathy. Semin Liver Dis 1996; 16:271.
  19. Jover R, Rodrigo R, Felipo V, et al. Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: A model of hepatic encephalopathy in cirrhosis. Hepatology 2006; 43:1257.
  20. Donovan JP, Schafer DF, Shaw BW Jr, Sorrell MF. Cerebral oedema and increased intracranial pressure in chronic liver disease. Lancet 1998; 351:719.
  21. Blei AT, Olafsson S, Therrien G, Butterworth RF. Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology 1994; 19:1437.
  22. Vogels BA, van Steynen B, Maas MA, et al. The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy. J Hepatol 1997; 26:387.
  23. Laubenberger J, Häussinger D, Bayer S, et al. Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology 1997; 112:1610.
  24. Moriyama M, Jayakumar AR, Tong XY, Norenberg MD. Role of mitogen-activated protein kinases in the mechanism of oxidant-induced cell swelling in cultured astrocytes. J Neurosci Res 2010; 88:2450.
  25. Wright G, Soper R, Brooks HF, et al. Role of aquaporin-4 in the development of brain oedema in liver failure. J Hepatol 2010; 53:91.
  26. Soria LR, Marrone J, Calamita G, Marinelli RA. Ammonia detoxification via ureagenesis in rat hepatocytes involves mitochondrial aquaporin-8 channels. Hepatology 2013; 57:2061.
  27. Blei AT, Larsen FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol 1999; 31:771.
  28. Larsen FS, Gottstein J, Blei AT. Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J Hepatol 2001; 34:548.
  29. Chu CJ, Wang SS, Lee FY, et al. Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure. Eur J Clin Invest 2001; 31:156.
  30. Rose C, Michalak A, Pannunzio M, et al. Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure. Hepatology 2000; 31:872.
  31. Häussinger D, Kircheis G, Fischer R, et al. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol 2000; 32:1035.
  32. Häussinger D, Roth E, Lang F, Gerok W. Cellular hydration state: an important determinant of protein catabolism in health and disease. Lancet 1993; 341:1330.
  33. Rama Rao KV, Jayakumar AR, Norenberg DM. Ammonia neurotoxicity: role of the mitochondrial permeability transition. Metab Brain Dis 2003; 18:113.
  34. Raabe W. Effects of hyperammonemia on neuronal function: NH4+, IPSP and Cl(-)-extrusion. Adv Exp Med Biol 1993; 341:71.
  35. Raabe W. Ammonium ions abolish excitatory synaptic transmission between cerebellar neurons in primary dissociated tissue culture. J Neurophysiol 1992; 68:93.
  36. Allert N, Köller H, Siebler M. Ammonia-induced depolarization of cultured rat cortical astrocytes. Brain Res 1998; 782:261.
  37. Mans AM, Biebuyck JF, Davis DW, et al. Regional cerebral glucose utilization in rats with portacaval anastomosis. J Neurochem 1983; 40:986.
  38. Lockwood AH, Ginsberg MD, Rhoades HM, Gutierrez MT. Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy. J Clin Invest 1986; 78:86.
  39. Görg B, Qvartskhava N, Keitel V, et al. Ammonia induces RNA oxidation in cultured astrocytes and brain in vivo. Hepatology 2008; 48:567.
  40. Reinehr R, Görg B, Becker S, et al. Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices. Glia 2007; 55:758.
  41. Görg B, Qvartskhava N, Bidmon HJ, et al. Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy. Hepatology 2010; 52:256.
  42. Görg B, Schliess F, Häussinger D. Osmotic and oxidative/nitrosative stress in ammonia toxicity and hepatic encephalopathy. Arch Biochem Biophys 2013; 536:158.
  43. Riggio O, Mannaioni G, Ridola L, et al. Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: a study on the pathophysiology of hepatic encephalopathy. Am J Gastroenterol 2010; 105:1374.
  44. Carpenedo R, Mannaioni G, Moroni F. Oxindole, a sedative tryptophan metabolite, accumulates in blood and brain of rats with acute hepatic failure. J Neurochem 1998; 70:1998.
  45. Moroni F, Carpenedo R, Venturini I, et al. Oxindole in pathogenesis of hepatic encephalopathy. Lancet 1998; 351:1861.
  46. Swapna I, Sathyasaikumar KV, Murthy ChR, et al. Changes in cerebral membrane lipid composition and fluidity during thioacetamide-induced hepatic encephalopathy. J Neurochem 2006; 98:1899.
  47. Swapna I, Kumar KV, Reddy PV, et al. Phospholipid and cholesterol alterations accompany structural disarray in myelin membrane of rats with hepatic encephalopathy induced by thioacetamide. Neurochem Int 2006; 49:238.
  48. Schafer DF, Pappas SC, Brody LE, et al. Visual evoked potentials in a rabbit model of hepatic encephalopathy. I. Sequential changes and comparisons with drug-induced comas. Gastroenterology 1984; 86:540.
  49. Schafer DF, Jones EA. Hepatic encephalopathy and the gamma-aminobutyric-acid neurotransmitter system. Lancet 1982; 1:18.
  50. Ferenci P, Püspök A, Steindl P. Current concepts in the pathophysiology of hepatic encephalopathy. Eur J Clin Invest 1992; 22:573.
  51. Zimmermann C, Ferenci P, Pifl C, et al. Hepatic encephalopathy in thioacetamide-induced acute liver failure in rats: characterization of an improved model and study of amino acid-ergic neurotransmission. Hepatology 1989; 9:594.
  52. Michalak A, Rose C, Butterworth J, Butterworth RF. Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 1996; 24:908.
  53. Butterworth RF. The astrocytic ("peripheral-type") benzodiazepine receptor: role in the pathogenesis of portal-systemic encephalopathy. Neurochem Int 2000; 36:411.
  54. Panickar KS, Jayakumar AR, Rama Rao KV, Norenberg MD. Downregulation of the 18-kDa translocator protein: effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes. Glia 2007; 55:1720.
  55. Püspök A, Herneth A, Steindl P, Ferenci P. Hepatic encephalopathy in rats with thioacetamide-induced acute liver failure is not mediated by endogenous benzodiazepines. Gastroenterology 1993; 105:851.
  56. Baraldi M, Zeneroli ML, Ventura E, et al. Supersensitivity of benzodiazepine receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat: reversal by a benzodiazepine antagonist. Clin Sci (Lond) 1984; 67:167.
  57. Bassett ML, Mullen KD, Skolnick P, Jones EA. Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 1987; 93:1069.
  58. Bosman DK, van den Buijs CA, de Haan JG, et al. The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat. Gastroenterology 1991; 101:772.
  59. Steindl P, Püspök A, Druml W, Ferenci P. Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: comparison with uremic encephalopathy. Hepatology 1991; 14:963.
  60. Basile AS, Gammal SH, Mullen KD, et al. Differential responsiveness of cerebellar Purkinje neurons to GABA and benzodiazepine receptor ligands in an animal model of hepatic encephalopathy. J Neurosci 1988; 8:2414.
  61. Basile AS, Pannell L, Jaouni T, et al. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Proc Natl Acad Sci U S A 1990; 87:5263.
  62. Basile AS, Hughes RD, Harrison PM, et al. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J Med 1991; 325:473.
  63. Yurdaydin C, Gu ZQ, Nowak G, et al. Benzodiazepine receptor ligands are elevated in an animal model of hepatic encephalopathy: relationship between brain concentration and severity of encephalopathy. J Pharmacol Exp Ther 1993; 265:565.
  64. Ahboucha S, Pomier-Layrargues G, Mamer O, Butterworth RF. Increased levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma. Neurochem Int 2006; 49:372.
  65. Keitel V, Görg B, Bidmon HJ, et al. The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 2010; 58:1794.
  66. Norenberg MD. Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996; 16:245.
  67. Bosman DK, Deutz NE, De Graaf AA, et al. Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatology 1990; 12:281.
  68. Moroni F, Lombardi G, Moneti G, Cortesini C. The release and neosynthesis of glutamic acid are increased in experimental models of hepatic encephalopathy. J Neurochem 1983; 40:850.
  69. de Knegt RJ, Schalm SW, van der Rijt CC, et al. Extracellular brain glutamate during acute liver failure and during acute hyperammonemia simulating acute liver failure: an experimental study based on in vivo brain dialysis. J Hepatol 1994; 20:19.
  70. Oppong KN, Bartlett K, Record CO, al Mardini H. Synaptosomal glutamate transport in thioacetamide-induced hepatic encephalopathy in the rat. Hepatology 1995; 22:553.
  71. Norenberg MD, Huo Z, Neary JT, Roig-Cantesano A. The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 1997; 21:124.
  72. Knecht K, Michalak A, Rose C, et al. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett 1997; 229:201.
  73. Chan H, Hazell AS, Desjardins P, Butterworth RF. Effects of ammonia on glutamate transporter (GLAST) protein and mRNA in cultured rat cortical astrocytes. Neurochem Int 2000; 37:243.
  74. Ferenci P, Pappas SC, Munson PJ, Jones EA. Changes in glutamate receptors on synaptic membranes associated with hepatic encephalopathy or hyperammonemia in the rabbit. Hepatology 1984; 4:25.
  75. Michalak A, Butterworth RF. Selective loss of binding sites for the glutamate receptor ligands [3H]kainate and (S)-[3H]5-fluorowillardiine in the brains of rats with acute liver failure. Hepatology 1997; 25:631.
  76. Saransaari P, Oja SS, Borkowska HD, et al. Effects of thioacetamide-induced hepatic failure on the N-methyl-D-aspartate receptor complex in the rat cerebral cortex, striatum, and hippocampus. Binding of different ligands and expression of receptor subunit mRNAs. Mol Chem Neuropathol 1997; 32:179.
  77. Cauli O, Rodrigo R, Llansola M, et al. Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy. Metab Brain Dis 2009; 24:69.
  78. Fan P, Szerb JC. Effects of ammonium ions on synaptic transmission and on responses to quisqualate and N-methyl-D-aspartate in hippocampal CA1 pyramidal neurons in vitro. Brain Res 1993; 632:225.
  79. Vogels BA, Maas MA, Daalhuisen J, et al. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 1997; 25:820.
  80. Hermenegildo C, Marcaida G, Montoliu C, et al. NMDA receptor antagonists prevent acute ammonia toxicity in mice. Neurochem Res 1996; 21:1237.
  81. Romero-Gómez M, Jover M, Del Campo JA, et al. Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. Ann Intern Med 2010; 153:281.
  82. Fischer JE, Baldessarini RJ. False neurotransmitters and hepatic failure. Lancet 1971; 2:75.
  83. Ferenci P, Wewalka F. Plasma amino acids in hepatic encephalopathy. J Neural Transm Suppl 1978; :87.
  84. Morgan MY, Milsom JP, Sherlock S. Plasma ratio of valine, leucine and isoleucine to phenylalanine and tyrosine in liver disease. Gut 1978; 19:1068.
  85. Cuilleret G, Pomier-Layrargues G, Pons F, et al. Changes in brain catecholamine levels in human cirrhotic hepatic encephalopathy. Gut 1980; 21:565.
  86. Zieve L, Olsen RL. Can hepatic coma be caused by a reduction of brain noradrenaline or dopamine? Gut 1977; 18:688.
  87. Montes S, Alcaraz-Zubeldia M, Muriel P, Ríos C. Striatal manganese accumulation induces changes in dopamine metabolism in the cirrhotic rat. Brain Res 2001; 891:123.
  88. Krieger D, Krieger S, Jansen O, et al. Manganese and chronic hepatic encephalopathy. Lancet 1995; 346:270.
  89. Rose C, Butterworth RF, Zayed J, et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology 1999; 117:640.
  90. Yurdaydin C, Hörtnagl H, Steindl P, et al. Increased serotoninergic and noradrenergic activity in hepatic encephalopathy in rats with thioacetamide-induced acute liver failure. Hepatology 1990; 12:695.
  91. Jellinger K, Riederer P, Kleinberger G, et al. Brain monoamines in human hepatic encephalopathy. Acta Neuropathol 1978; 43:63.
  92. Rao VL, Butterworth RF. Alterations of [3H]8-OH-DPAT and [3H]ketanserin binding sites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Neurosci Lett 1994; 182:69.
  93. Rao VL, Giguère JF, Layrargues GP, Butterworth RF. Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Brain Res 1993; 621:349.
  94. Bergqvist PB, Hjorth S, Wikell C, et al. p-Chloroamphetamine- and d-fenfluramine-induced brain serotonin release in experimental portal-systemic encephalopathy. Metab Brain Dis 1997; 12:229.
  95. Bergqvist PB, Hjorth S, Apelqvist G, Bengtsson F. Potassium-evoked neuronal release of serotonin in experimental chronic portal-systemic encephalopathy. Metab Brain Dis 1997; 12:193.
  96. Yurdaydin C, Herneth AM, Püspök A, et al. Modulation of hepatic encephalopathy in rats with thioacetamide-induced acute liver failure by serotonin antagonists. Eur J Gastroenterol Hepatol 1996; 8:667.
  97. Mousseau DD, Butterworth RF. The [3H]tryptamine receptor in human brain: kinetics, distribution, and pharmacologic profile. J Neurochem 1994; 63:1052.
  98. Michalak A, Chatauret N, Butterworth RF. Evidence for a serotonin transporter deficit in experimental acute liver failure. Neurochem Int 2001; 38:163.
  99. Lozeva V, Tuomisto L, Sola D, et al. Increased density of brain histamine H(1) receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy. Hepatology 2001; 33:1370.
  100. Córdoba J, Cabrera J, Lataif L, et al. High prevalence of sleep disturbance in cirrhosis. Hepatology 1998; 27:339.
  101. Steindl PE, Finn B, Bendok B, et al. Disruption of the diurnal rhythm of plasma melatonin in cirrhosis. Ann Intern Med 1995; 123:274.
  102. Horowitz ME, Schafer DF, Molnar P, et al. Increased blood-brain transfer in a rabbit model of acute liver failure. Gastroenterology 1983; 84:1003.
  103. Goldbecker A, Buchert R, Berding G, 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.
  104. James JH, Escourrou J, Fischer JE. Blood-brain neutral amino acid transport activity is increased after portacaval anastomosis. Science 1978; 200:1395.
  105. Hawkins RA, Jessy J. Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis. Biochem J 1991; 277 ( Pt 3):697.
  106. Hawkins RA, Jessy J, Mans AM, De Joseph MR. Effect of reducing brain glutamine synthesis on metabolic symptoms of hepatic encephalopathy. J Neurochem 1993; 60:1000.
  107. Iversen P, Sørensen M, Bak LK, et al. Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology 2009; 136:863.
  108. Hindfelt B, Plum F, Duffy TE. Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J Clin Invest 1977; 59:386.
  109. Karagiannis A, Sylantyev S, Hadjihambi A, et al. Hemichannel-mediated release of lactate. J Cereb Blood Flow Metab 2016; 36:1202.
  110. Hadjihambi A, De Chiara F, Hosford PS, et al. Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease. Hepatology 2017; 65:1306.
  111. Merli M, Lucidi C, Pentassuglio I, et al. Increased risk of cognitive impairment in cirrhotic patients with bacterial infections. J Hepatol 2013; 59:243.
  112. Wasmuth HE, Kunz D, Yagmur E, et al. Patients with acute on chronic liver failure display "sepsis-like" immune paralysis. J Hepatol 2005; 42:195.
  113. Iacobone E, Bailly-Salin J, Polito A, et al. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med 2009; 37:S331.
  114. Papadopoulos MC, Davies DC, Moss RF, et al. Pathophysiology of septic encephalopathy: a review. Crit Care Med 2000; 28:3019.
  115. Licinio J, Wong ML. Pathways and mechanisms for cytokine signaling of the central nervous system. J Clin Invest 1997; 100:2941.
  116. Didier N, Romero IA, Créminon C, et al. Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J Neurochem 2003; 86:246.
  117. Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 2007; 22:125.
  118. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004; 40:247.
  119. Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol 1987; 4:8.
  120. Stadlbauer V, Mookerjee RP, Wright GA, et al. Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2009; 296:G15.
  121. Wright G, Davies NA, Shawcross DL, et al. Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology 2007; 45:1517.
  122. Rodrigo R, Cauli O, Gomez-Pinedo U, et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 2010; 139:675.
  123. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010; 51:1062.
  124. Shawcross DL, Wright GA, Stadlbauer V, et al. Ammonia impairs neutrophil phagocytic function in liver disease. Hepatology 2008; 48:1202.
  125. Monfort P, Cauli O, Montoliu C, et al. Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: therapeutical implications. Neurochem Int 2009; 55:106.
  126. Gupta A, Dhiman RK, Kumari S, et al. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol 2010; 53:849.
  127. Bajaj JS, Hylemon PB, Ridlon JM, et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 2012; 303:G675.
  128. Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012; 302:G168.
  129. Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60:940.
  130. Bajaj JS, Betrapally NS, Hylemon PB, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 2015; 62:1260.