Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

Authors

  • T. V. Shulyatnikova Zaporizhzhia State Medical University, Ukraine,
  • V. A. Shavrin Zaporizhzhia State Medical University, Ukraine,

DOI:

https://doi.org/10.14739/2310-1237.2017.3.118773

Keywords:

hepatic encephalopathy, ammonia

Abstract

Background. The problem of acute and chronic forms of hepatic encephalopathy (HE) is not clearly identified among modern problems of hepatology and neuroscience in Ukraine. Despite the significant contribution to the development of lethal complications in patients with liver pathology and long history of the study of this issue, there is still no unified opinion on the links of HE pathogenesis.

The aim of this review is to conduct a comprehensive analysis of current data on the spreading and mechanisms of development of HE.

HE is a complex of potentially reversible neurocognitive disorders in patients with chronic or acute hepatic failure (ALF). HE is more often a complication of liver cirrhosis and is the second most frequent cause of hospitalization of such patients after ascites. When decompensating liver failure in acute or chronic hepatic pathology in patients severe forms of HE develop, accompanied by a progressive increase in intracranial pressure and the development of coma, which often ends lethal due to poor corrigibility of intracranial hypertension while maintaining hepatogenic neurointoxication. HE is considered as the end result of the accumulation of a number of neurotoxic substances in the brain, among which are ammonia, mercaptans, short chain fatty acids, false neurotransmitters, gamma-aminobutyric acid, manganese. The most popular among the reasons for the development of HE is the neurotoxic theory of ammonia. Ammonia is subjected to detoxification in the liver, turning into urea, a smaller fraction with the participation of glutamine synthetase is used in the synthesis of glutamine in muscles, liver and astrocytes of brain. In case of hepatic dysfunction and/or portosystemic shunting, the concentration of ammonia in blood increases up to 10 times and the main load for its detoxification is shifted to myocytes and astroglia. In ALF glutamine overload of astrocytes occurs with a change in intracellular osmolarity and subsequent edema of astroglia, which is accompanied by the development of cytotoxic edema of the brain. In this case, in astrocytes damaging of mitochondrial respiratory chain occurs and mitochondrial insufficiency develops, as well as processes of nitrosative-oxidative stress and oxidation of astrocytic and neuronal RNA, disruption of gene expression, synthesis of neuro- and gliotransmitters and synaptic plasticity. The increased influx of aromatic amino acids into brain leads to the synthesis of false neurotransmitters, which worsens serotoninergic, GABA-ergic, dopaminergic and glutamatergic neurotransmission. Damage to the components of the blood-brain barrier leads to aggravation of the water imbalance, penetration of hematogenous cytokines, endotoxins and other products of systemic inflammatory reaction into the cerebral parenchyma and development of neuroinflammation, which makes an important contribution to the further progression of cerebral edema.

Conclusions: despite a comprehensive study of the problem, many open questions remain in the pathogenesis of HE. Special attention should be paid to more detailed study of the mechanisms of formation and elimination of edematous changes in brain tissue on the background of hepatogenic intoxication and the development of a systemic inflammatory reaction, the role of astroglia and its water channels in these processes, as well as the mechanisms of damage to the blood-brain barrier.

References

  1. Ferenci, P. (2017). Hepatic encephalopathy. Gastroenterology Report, 5(2), 138–147. doi: http://doi.org/10.1093/gastro/gox013
  2. Butterworth, R. (2016). Neurosteroids in hepatic encephalopathy: Novel insights and new therapeutic opportunities. The Journal of Steroid Biochemistry and Molecular Biology, 160, 94–97. doi: 10.1016/j.jsbmb.2015.11.006.
  3. Volk, M., Tocco, R., Bazick, J., Rakoski, M., & Lok, A. (2012). Hospital Readmissions Among Patients With Decompensated Cirrhosis. The American Journal of Gastroenterology, 107(2), 247–252. doi: 10.1038/ajg.2011.314
  4. Stepanova, M., Mishra, A., Venkatesan, C., & Younossi, Z. M. (2012) In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin Gastroenterol Hepatol., 10, 1034–1041. doi: 10.1016/j.cgh.2012.05.016.
  5. Hassan, E., Abd El-Rehim, A., Seifeldein, G., & Shehata, G. (2014). Minimal hepatic encephalopathy in patients with liver cirrhosis: Magnetic resonance spectroscopic brain findings versus neuropsychological changes. Arab Journal of Gastroenterology, 15(3-4), 108–113. doi: 10.1016/j.ajg.2014.09.003
  6. Elwir, S., & Rahimi, R. S. (2017). Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. Journal of Clinical and Translational Hepatology, 5(2), 142–151. doi: 10.14218/JCTH.2016.00069
  7. Bustamante, J., Rimola, A., Ventura, P., Navasa, M., Cirera, I., Reggiardo, V., & Rodés, J. (1999). Prognostic significance of hepatic encephalopathy in patients with cirrhosis. Journal of Hepatology, 30(5), 890–895.
  8. Kaplan, P., & Rossetti, A. (2011). EEG Patterns and Imaging Correlations in Encephalopathy. Journal of Clinical Neurophysiology, 28(3), 233–251. doi: 10.1097/WNP.0b013e31821c33a0
  9. Ding, A., Lee, A., Callender, M., Loughrey, M., Quah, S., & Dinsmore, W. (2010). Hepatic encephalopathy as an unusual late complication of transjugular intrahepatic portosystemic shunt insertion for non-cirrhotic portal hypertension caused by nodular regenerative hyperplasia in an HIV-positive patient on highly active antiretroviral therapy. International Journal of STD & AIDS, 21(1), 71–72. doi: 10.1258/ijsa.2009.009038
  10. Ferenci, P., Litwin, T., Seniow, J., & Czlonkowska, A. ( 2015). Encephalopathy in Wilson Disease: Copper Toxicity or Liver Failure? Journal of Clinical and Experimental Hepatology, 5 (Suppl 1), S88-S95. doi: 10.1016/j.jceh.2014.09.002
  11. Upadhyay, R., Bleck, T., & Busl, K. (2016). Hyperammonemia: What Urea-lly Need to Know: Case Report of Severe Noncirrhotic Hyperammonemic Encephalopathy and Review of the Literature. Case Reports in Medicine, 2016, 1–10. doi: http://doi.org/10.1155/2016/8512721
  12. Wendon, J., Cordoba, J., Dhawan, A., Larsen, F., Manns, M., Nevens, F., et al. (2017). EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. Journal of Hepatology, 66(5), 1047–1081. doi: 10.1016/j.jhep.2016.12.003.
  13. Vilstrup, H., Amodio, P., Bajaj, J., Cordoba, J., Ferenci, P., Mullen, K., et al. (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(2), 715–735. doi: 10.1002/hep.27210.
  14. Bajaj, J., Cordoba, J., Mullen, K., Amodio, P., Shawcross, D., Butterworth, R., & Morgan, M. (2011). Review article: the design of clinical trials in hepatic encephalopathy - an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Alimentary Pharmacology & Therapeutics, 33(7), 739–747. doi: 10.1111/j.1365-2036.2011.04590.x.
  15. Perazzo, J., Tallis, S., Delfante, A., Souto, P. A., Lemberg, A., Eizayaga, F. X., & Romay, S. (2012). Hepatic encephalopathy: An approach to its multiple pathophysiological features. World Journal of Hepatology, 4(3), 50–65. doi: 10.4254/wjh.v4.i3.50
  16. Ramachandran, A., & Jaeschke, H. (2017). Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology. Journal of Clinical and Translational Research, 3 (Suppl 1), 157–169. doi: 10.18053/jctres.03.2017S1.002
  17. Elwir, S., & Rahimi, R. S. (2017). Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. Journal of Clinical and Translational Hepatology, 5(2), 142–151. doi: 10.14218/JCTH.2016.00069
  18. Khan, A., Ayub, M., & Khan, WM (2016). Hyperammonemia Is Associated with Increasing Severity of Both Liver Cirrhosis and Hepatic Encephalopathy. International. Journal of Hepatology, 2016, 6741754. doi: 10.1155/2016/6741754
  19. Acharya, G., Mehra, S., Patel, R., Frunza-Stefan, S., & Kaur, H. (2016). Fatal Nonhepatic Hyperammonemia in ICU Setting: A Rare but Serious Complication following Bariatric Surgery. Case Reports in Critical Care, 2016 (2016), doi: 10.1155/2016/8531591
  20. Dam, G., Keiding, S., Munk, O. L., Ott, P., Vilstrup, H., Bak, L. K., et al. (2013). Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake. Hepatology, 57(1), 258–265. doi: 10.1002/hep.25995.
  21. Walker, V. (2014) Ammonia metabolism and hyperammonemic disorders. Adv Clin Chem., 67, 73–150. doi: 10.1016/bs.acc.2014.09.002.
  22. Wright, G., Noiret, L., Olde Damink, S., & Jalan, R. (2011). Interorgan ammonia metabolism in liver failure: the basis of current and future therapies. Liver International, 31(2), 163–175. doi: 10.1111/j.1478-3231.2010.02302.x
  23. Bosoi, C. R., & Rose, C. (2009). Identifying the direct effects of ammonia on the brain. Metabolic Brain Disease, 24, 95–102. doi: 10.1007/s11011-008-9112-7
  24. Saparov, S., Liu, K., Agre, P., & Pohl, P. (2007). Fast and Selective Ammonia Transport by Aquaporin-8. Journal of Biological Chemistry, 282(8), 5296–5301. doi: 10.1074/jbc.M609343200
  25. Scott, T. R., Kronsten, V. T., Hughes, R. D., & Shawcross, D. L. (2013). Pathophysiology of cerebral oedema in acute liver failure. Journal of Gastroenterology world: WJG, 19(48), 9240–9255. doi: 10.3748/wjg.v19.i48.9240
  26. Norenberg, M. D. (1998) Astroglial dyfunction in hepatic encephalopathy. Metab Brain Dis., 13(4), 319–335.
  27. Desjardins, P., Du, T., Jiang, W., Peng, L., & Butterworth, R. F. (2012). Jiang Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem Int., 60, 690–696. doi: 10.1016/j.neuint.2012.02.001.
  28. Blei, A. T., Olafsson, S., Therrien, G., & Butterworth, R. F. (1994). Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology, 19(6), 1437–1444. doi: 10.1002/hep.1840190619
  29. Bustamante, J., Lores-Arnaiz, S., Tallis, S., Roselló, D. M., Lago, N., Lemberg, A., et al. (2011). Mitochondrial dysfunction as a mediator of hippocampal apoptosis in a model of hepatic encephalopathy. Mol the Cell Biochem, 354(1-2), 231–240. doi: 10.1007/s11010-011-0822-5.
  30. Görg, B., Schliess, F., & Häussinger, D. (2013). Osmotic and oxidative/nitrosative stress in ammonia toxicity and hepatic encephalopathy. Arch Biochem Biophys, 536(2), 158–63. doi: 10.1016/j.abb.2013.03.010
  31. Rose, C., Kresse, W., & Kettenmann, H. (2005). Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH. J. Biol. Chem., 280(22), 20937–20944. doi: 10.1074/jbc.M412448200
  32. Montana, V., Verkhratsky, A., & Parpura, V. (2014). Pathological Role for Exocytotic Glutamate Release from Astrocytes in Hepatic Encephalopathy. Neuropharmacology Current, 12(4), 324–333. doi: 10.2174/1570159X12666140903094700
  33. Thrane, V. R., Thrane, A. S., Wang, F., Cotrina, M. L., Smith, N. A., Chen, M., et al. (2013). Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. Nature Medicine, 19, 1643–1648 doi: 10.1038/nm.3400
  34. Basile, A., Hughes, R., Harrison, P., Murata, Y., Pannell, L., Jones, E., et al. (1991). Elevated Brain Concentrations of 1,4-Benzodiazepines in Fulminant Hepatic Failure. New England Journal of Medicine, 325(7), 473–478. doi: 10.1056/NEJM199108153250705
  35. Jayakumar, A. R., Ruiz-Cordero, R., Tong, X. Y., & Norenberg, M. D. (2013). Brain Edema in Acute Liver Failure: Role of Neurosteroids. Archives of Biochemistry and Biophysics, 536(2), 171–175. doi: 10.1016/j.abb.2013.03.007
  36. Skowrońska, M., & Albrecht, J. (2012). Alterations of blood brain barrier function in hyperammonemia: an overview. Neurotoxicity Research, 21(2), 236–244. doi: 10.1007/s12640-011-9269-4
  37. Verkhratsky, A., Matteoli, M., Parpura, V., Mothet, J., & Zorec, R. (2016). Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion. The EMBO Journal, 35(3), 239–257. doi: 10.15252/embj.201592705.
  38. Noell, S., Wolburg-Buchholz, K., Mack, A. F., Beedle, A. M., Satz, J. S., Campbell, K. P., & Fallier-Becker, P. (2011). Evidence for a role of dystroglycan regulating the membrane architecture of astroglial endfeet. The European Journal of Neuroscience, 33(12), 2179–2186. doi: 10.1111/j.1460-9568.2011.07688.x.
  39. Ren, Z., Iliff, J., Yang, L., Yang, J., Chen, X., Chen, M., et al. (2013). ‘Hit & Run’ Model of Closed-Skull Traumatic Brain Injury (TBI) Reveals Complex Patterns of Post-Traumatic AQP4 Dysregulation. Journal of Cerebral Blood Flow & Metabolism, 33(6), 834–845. doi: 10.1038/jcbfm.2013.30
  40. Li, L., Zhang, H., Varrin-Doyer, M., Zamvil, S. S., & Verkman, A. S. (2011). Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. The FASEB Journal, 25(5), 1556–1566. doi: 10.1096/fj.10-177279
  41. Filippidis, A. S., Carozza, R. B., & Rekate, H. L. (2016). Aquaporins in Brain Edema and Neuropathological Conditions. Journal of Molecular International Sciences, 18(1), 55. doi: 10.3390/ijms18010055
  42. Rama Rao, K. V., Chen, M., Simard, J. M., & Norenberg, M. D. (2003) Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport, 19, 14(18), 2379–82. doi: 10.1097/01.wnr.0000099610.19426.a6
  43. Bodega, G., Suárez, I, López-Fernández, L. A., García, M. I., Köofber, M., Penedo, M., et al. (2012) Ammonia induces aquaporin-4 rearrangement in the plasma membrane of cultured astrocytes. Neurochem. Int, 61, 1314–1324. doi: 10.1016/j.neuint.2012.09.008
  44. Wright, G., Soper, R., Brooks, H. F., Stadlbauer, V., Vairappan, B., Davies, N. A., et al. (2010). Role of aquaporin-4 in the development of brain oedema in liver failure. J Hepatol, 53, 91–97. doi: 10.1016/j.jhep.2010.02.020
  45. Iliff, J. J., & Nedergaard, M. (2013). Is there a cerebral lymphatic system? Stroke; a Journal of Cerebral Circulation, 44(601), S93–S95. doi: 10.1161/STROKEAHA.112.678698
  46. Stokum, J. A., Kurland, D. B., Gerzanich, V., & Simard, J. M. (2015). Mechanisms of Astrocyte-Mediated Cerebral Edema. Neurochemical Research, 40(2), 317–328. doi: 10.1007/s11064-014-1374-3
  47. Thumburu, K. K., Dhiman, R. K., Vasishta, R. K., Chakraborti, A., Butterworth, R. F., Beauchesne, E., et al. (2014). Expression of astrocytic genes coding for proteins implicated in neural excitation and brain edema is altered after acute liver failure. J Neurochem, 128(5), 617–627. doi: 10.1111/jnc.12511.
  48. Butterworth, R. F. (2015). Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure. Journal of Clinical and Experimental Hepatology, 5(Suppl 1), S96–S103. doi: 10.1016/j.jceh.2014.02.004
  49. Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., et al. (2012). A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Science Translational Medicine, 4(147), 147ra111. doi: 10.1126/scitranslmed.3003748
  50. Goldbecker, A., Buchert, R., Berding, G., Bokemeyer, M., Lichtinghagen, R., Wilke, F., et al. (2010). Blood–brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 30(7), 1384–1393. doi: 10.1038/jcbfm.2010.22
  51. Castejón, O. J. (2012). Ultrastructural pathology of endothelial tight junctions in human brain oedema. Folia Neuropathol, 50(2), 118–129.
  52. Brkic, M., Balusu, S., Libert, C., & Vandenbroucke, R. E. (2015). Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases. Mediators of Inflammation, 2015, 620581. doi: 10.1155/2015/620581.
  53. Nguyen, J. H., Yamamoto, S., Steers, J., Sevlever, D., Lin, W., Shimojima, N., et al. (2006). Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. Journal of Hepatology, 44(6), 1105–1114. doi: 10.1016/j.jhep.2005.09.019
  54. Jayakumar, A. R., Tong, X. Y., Ospel, J., & Norenberg, M. D. (2012). Role of Cerebral Endothelial Cells in the Astrocyte Swelling and Brain Edema Associated with Acute Hepatic Encephalopathy. Neuroscience, 218, 305–316. doi: 10.1016/j.neuroscience.2012.05.006.
  55. Larsen, F. S., Gottstein, J., & Blei, A. T. (2001). Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. Journal Of Hepatology, 34(4), 548–554. doi: 10.1016/S0168-8278(00)00069-6
  56. Zemtsova, I., Gorg, B., Keitel, V., Bidmon, H. J., Schror, K., & Haussinger, D. (2011). Microglia activation in hepatic encephalopathy in rats and humans. Hepatology, 54(1), 204–215. doi: 10.1002/hep.24326.
  57. Dennis, C. V., Sheahan, P. J., Graeber, M. B., Sheedy, D. L., Kril, J. J., & Sutherland, G. T. (2014). Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy. Metabolic Brain Disease, 29(4), 1027–1039. doi: 10.1007/s11011-013-9469-0
  58. Verderio, C., Cagnoli, C., Bergami, M., Francolini, M., Schenk, U., Colombo, A. et al. (2012). TI's - the VAMP/VAMP7 is the SNARE of secretory lysosomes contributing to ATP secretion from astrocytes. Biol Cell, 104(4), 213–28. doi: 10.1111/boc.201100070
  59. Sarkar, A., Mitra, S., Mehta, S., Raices, R., & Wewers, M. D. (2009). Monocyte Derived Microvesicles Deliver a Cell Death Message via Encapsulated Caspase-1. PLoS ONE, 4(9), e7140. doi: 10.1371/journal.pone.0007140
  60. Butterworth, R. F. (2011). Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology, 53(4), 1372–1376. doi: 10.1002/hep.24228
  61. Shawcross, D. L., Sharifi, Y., Canavan, J. B., Yeoman, A. D., Abeles, R. D., Taylor, N. J., et al. (2011). Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. Journal of hepatology, 54(4), 640–649. doi: 10.1016/j.jhep.2010.07.045
  62. Wright, G., Davies, N. A., Shawcross, D. L., Hodges, S. J., Zwingmann, C., Brooks, H. F., et al. (2007). Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology, 45(6), 1517–1526. doi: 10.1002/hep.21599
  63. Donnelly, M. C., Hayes, P. C., & Simpson, K. J. (2016). Role of inflammation and infection in the pathogenesis of human acute liver failure: Clinical implications for monitoring and therapy. World Journal of Gastroenterology, 22(26), 5958–5970. doi: 10.3748/wjg.v22.i26.5958
  64. Aldridge, D. R., Tranah, E. J., & Shawcross, D. L. (2015). Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation. Journal of Clinical and Experimental Hepatology, 5(Suppl 1), S7–S20. doi: 10.1016/j.jceh.2014.06.004
  65. Bajaj, J. S. (2014). The role of microbiota in hepatic encephalopathy. Gut Microbes, 5(3), 397–403. doi: 10.4161/gmic.28684.

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Shulyatnikova TV, Shavrin VA. Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis. Pathologia [Internet]. 2017Dec.22 [cited 2026May20];14(3). Available from: https://pat.zsmu.edu.ua/article/view/118773

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Vol. 14 No. 3 (2017)

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