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Neuroinflammation in the Pathogenesis of Hepatic Encephalopathy

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Hepatic Encephalopathy

Part of the book series: Clinical Gastroenterology ((CG))

Abstract

Central nervous system (CNS) complications of liver failure include hepatic encephalopathy (HE) and brain edema. Recent research driven primarily by studies in experimental animal models suggests that inflammation, acting alone or in concert with ammonia, plays a key role in the pathogenesis of these complications. It is well established that systemic inflammation worsens encephalopathy and brain edema and its complications in acute liver failure (ALF) and more recently, evidence for the presence of neuroinflammation (inflammatory processes in the brain per se) has been accumulating. Evidence in favor of neuroinflammatory mechanisms includes the finding of microglial activation in brain (microglia are the immunomodulator cells of the brain) together with increased brain accumulation of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. Although the precise nature of the signaling mechanisms between the failing liver and the brain leading to neuroinflammation is unknown, mechanisms involving blood–brain cytokine transfer and brain lactate have been proposed. Neuroinflammatory responses in liver failure result in upregulation of translocator protein (TLP), a mitochondrial membrane protein that is particularly concentrated in microglia. Positron emission tomography studies using the TLP ligand C-PK11195 in cirrhotic patients with mild HE reveal increased signals consistent with microglial activation and neuroinflammation. It has been proposed that existing therapies for HE including lactulose, rifaximin, albumen dialysis, and probiotics have the potential to lower both circulating ammonia and proinflammatory cytokines. Moreover, mild hypothermia and N-acetylcysteine have similar joint actions. Treatment of experimental animals with liver failure due to liver ischemia or toxic liver injury reveals that minocycline, an agent with potent inhibitory actions on microglial activation or the TNF-α receptor antagonist etanercept, leads to slowing of progression of encephalopathy and brain edema in ALF. Translation of these findings to the clinic has the potential to provide novel strategies for the management and treatment of the CNS complications of liver failure in the future.

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References

  1. Kato M, Hughes RD, Keays RT, Williams R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology. 1992;15:1060–6.

    Article  PubMed  CAS  Google Scholar 

  2. Cordoba J, Blei AT. Brain edema and hepatic encephalopathy. Semin Liver Dis. 1996;16:271–80.

    Article  PubMed  CAS  Google Scholar 

  3. Kril JJ, Butterworth RF. Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease. Hepatology. 1997;26(4):837–41.

    Article  PubMed  CAS  Google Scholar 

  4. Butterworth RF. Thiamine deficiency-related brain dysfunction in chronic liver failure. Metab Brain Dis. 2009;24(1):189–96.

    Article  PubMed  CAS  Google Scholar 

  5. Jiang W, Qu H, Desjardins P, Chatauret N, Bélanger M, Butterworth RF. Beneficial effects of mild hypothermia on the expression of pro-inflammatory cytokines in rats with acute liver failure. Hepatology. 2005;42(4 Suppl 1):361A.

    Google Scholar 

  6. Jiang W, Desjardins P, Butterworth RF. Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab. 2009;29:944–52.

    Article  PubMed  CAS  Google Scholar 

  7. Bémeur C, Qu H, Desjardins P, Butterworth RF. IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. Neurochem Int. 2010;56:213–5.

    Article  PubMed  Google Scholar 

  8. Butterworth RF. Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology. 2011;53(4):1372–6.

    Article  PubMed  Google Scholar 

  9. D’Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci. 2009;29:2089–102.

    Article  PubMed  Google Scholar 

  10. Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia-Verdugo JM, et al. Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology. 2010;139:675–84.

    Article  PubMed  CAS  Google Scholar 

  11. Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000;32:734–9.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Bernal W, Donaldson P, Underhill J, Wendon J, Williams R. Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. J Hepatol. 1998;29(1):53–9.

    Article  PubMed  CAS  Google Scholar 

  14. Chu CJ, Chen CT, Wang SS, Lee FY, Chang FY, Lin HC, et al. Hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: role of endotoxin and tumor necrosis factor-alpha. Zhonghua Yi Xue Za Zhi (Taipei). 2001;64(6):321–30.

    CAS  Google Scholar 

  15. Bémeur C, Qu H, Desjardins P, Butterworth RF. Contribution of cerebral proinflammatory cytokines to hepatic encephalopathy in experimental acute liver failure: effect of interleukin-1beta receptor and tumor necrosis factor-alpha receptor knockouts. Hepatology. 2008;48(4 Suppl):348A.

    Google Scholar 

  16. Wright G, Shawcross D, Olde Damink SW, Jalan R. Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis. 2007;22:375–88.

    Article  PubMed  CAS  Google Scholar 

  17. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology. 2010;51:1062–9.

    Article  PubMed  CAS  Google Scholar 

  18. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40:247–54.

    Article  PubMed  CAS  Google Scholar 

  19. Morita H, Hosoya M, Kato A, Kawasaki Y, Suzuki H. Laboratory characteristics of acute encephalopathy with multiple organ dysfunctions. Brain Dev. 2005;27:477–82.

    Article  PubMed  Google Scholar 

  20. Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis. 2007;22:125–38.

    Article  PubMed  CAS  Google Scholar 

  21. Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, et al. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011;54(4):640–9. doi:10.1016/j.jhep. 2010.07.045.

    Article  PubMed  CAS  Google Scholar 

  22. Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology. 2007;46:514–9.

    Article  PubMed  CAS  Google Scholar 

  23. Brück J, Görg B, Bidmon HJ, Zemtsova I, Qvartskhava N, Keitel V, et al. Locomotor impairment and cerebrocortical oxidative stress in portal vein ligated rats in vivo. J Hepatol. 2011;54(2):251–7. doi:10.1016/j.jhep. 2010.06.035.

    Article  PubMed  Google Scholar 

  24. Jover R, Rodrigo R, Felipo V, Insausti R, Sáez-Valero J, García-Ayllón MS, 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(6):1257–66.

    Article  PubMed  CAS  Google Scholar 

  25. Atanassov CL, Muller CD, Dumont S, Rebel G, Poindron P, Seiler N. Effect of ammonia on endocytosis and cytokine production by immortalized human microglia and astroglia cells. Neurochem Int. 1995;27(4–5):417–24.

    Article  PubMed  CAS  Google Scholar 

  26. Andersson AK, Rönnbäck L, Hansson E. Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures. J Neurochem. 2005;93:1327–33.

    Article  PubMed  CAS  Google Scholar 

  27. Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett. 1997;229(3):201–3.

    Article  PubMed  CAS  Google Scholar 

  28. Jiang W, Desjardins P, Butterworth RF. Molecular basis of synergism between brain ammonia and proinflammatory mechanisms in acute liver failure. Hepatology. 2009;50(4 Suppl):430A.

    Google Scholar 

  29. Norenberg MD, Baker L, Norenberg LO, Blicharska J, Bruce-Gregorios JH, Neary JT. Ammonia-induced astrocyte swelling in primary culture. Neurochem Res. 1991;16:833–6.

    Article  PubMed  CAS  Google Scholar 

  30. Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC. Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation. 2000;7:153–9.

    Article  PubMed  CAS  Google Scholar 

  31. Chastre A, Grimm A, Bémeur C, Desjardins P, Butterworth RF. Beneficial effect of soluble TNF receptor (Etanercept) on neurological complications of acute liver failure resulting from toxic liver injury in mice. Hepatology. 2010;52:1086A.

    Google Scholar 

  32. van Rossum D, Hanisch UK. Microglia. Metab Brain Dis. 2004;19:393–411.

    Article  PubMed  Google Scholar 

  33. Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF. Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Gastroenterology. 2003;125(3):815–24.

    Article  PubMed  CAS  Google Scholar 

  34. Therrien G, Giguère JF, Butterworth RF. Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy. Metab Brain Dis. 1991;4:225–31.

    Article  Google Scholar 

  35. Lai JC, Cooper AJ. Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem. 1986;47:1376–86.

    Article  PubMed  CAS  Google Scholar 

  36. Chatauret N, Rose C, Therrien G, Pannunzio M, Butterworth RF. Mild hypothermia prevents cerebral edema and CSF lactate accumulation in acute liver failure. Metab Brain Dis. 2001;16:95–102.

    Article  PubMed  CAS  Google Scholar 

  37. Filipov NM, Seegal RF, Lawrence DA. Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. Toxicol Sci. 2005;84:139–48.

    Article  PubMed  CAS  Google Scholar 

  38. Pomier Layrargues G, Spahr L, Butterworth RF. Increased manganese concentrations in pallidum of cirrhotic patients: cause of magnetic resonance hyperintensity? Lancet. 1995;345:735.

    Article  PubMed  CAS  Google Scholar 

  39. Lavoie J, Pomier Layrargues G, Butterworth RF. Increased densities of “peripheral-type” benzodiazepine receptors in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology. 1990;11:874–8.

    Article  PubMed  CAS  Google Scholar 

  40. Cagnin A, Taylor-Robinson SD, Forton DM, Banati RB. In vivo imaging of cerebral “peripheral benzodiazepine binding sites” in patients with hepatic encephalopathy. Gut. 2006;55:547–53.

    Article  PubMed  CAS  Google Scholar 

  41. Bélanger M, Ahboucha S, Desjardins P, Butterworth RF. Upregulation of peripheral-type (mitochondrial) benzodiazepine receptors in hyperammonemic syndromes: consequences for neuronal excitability. Adv Mol Cell Biol. 2004;31(3):983–97.

    Google Scholar 

  42. Giguère JF, Hamel E, Butterworth RF. Increased densities of binding sites for the “peripheral-type” benzodiazepine receptor ligand 3H-PK 11195 in rat brain following portacaval anastomosis. Brain Res. 1992;585:295–8.

    Article  PubMed  Google Scholar 

  43. Desjardins P, Bandeira P, Raghavendra Rao VL, Ledoux S, Butterworth RF. Increased expression of the peripheral-type benzodiazepine receptor-isoquinoline carboxamide binding protein in mRNA brain following portacaval anastomosis. Brain Res. 1997;758:255–8.

    Article  PubMed  CAS  Google Scholar 

  44. Jiang W, Desjardins P, Butterworth RF. Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem. 2009;109:485–93.

    Article  PubMed  CAS  Google Scholar 

  45. Bélanger M, Desjardins P, Chatauret N, Butterworth RF. Loss of expression of glial fibrillary acidic protein in acute hyperammonemia. Neurochem Int. 2002;41(2–3):155–60.

    Article  PubMed  Google Scholar 

  46. Kril JJ, Flowers D, Butterworth RF. Distinctive pattern of Bergmann glial pathology in human hepatic encephalopathy. Mol Chem Neuropathol. 1997;31(3):279–87.

    Article  PubMed  CAS  Google Scholar 

  47. Butterworth RF, Giguère JF, Michaud J, Lavoie J, Pomier Layrargues G. Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol. 1987;6:1–12.

    Article  PubMed  CAS  Google Scholar 

  48. Doorduin J, de Vries EF, Dierckx RA, Klein HC. PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des. 2008;14(31):3297–315.

    Article  PubMed  CAS  Google Scholar 

  49. Ahboucha S, Pomier-Layrargues G, Mamer O, Butterworth RF. Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol. 2005;58(1):169–70.

    Article  PubMed  CAS  Google Scholar 

  50. Ahboucha S, Jiang W, Chatauret N, Mamer O, Baker GB, Butterworth RF. Indomethacin improves locomotor deficit and reduces brain concentrations of neuroinhibitory steroids in rats following portacaval anastomosis. Neurogastroenterol Motil. 2008;20:949–57.

    Article  PubMed  CAS  Google Scholar 

  51. Cauli O, Rodrigo R, Piedrafita B, Llansola M, Mansouri MT, Felipo V. Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy: ibuprofen restores its motor activity. J Neurosci Res. 2009;87:1369–74.

    Article  PubMed  CAS  Google Scholar 

  52. Norenberg MD. Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis. 1998;13(4):319–35.

    Article  PubMed  CAS  Google Scholar 

  53. Hazell AS. Astrocytes and manganese neurotoxicity. Neurochem Int. 2002;41(4):271–7.

    Article  PubMed  CAS  Google Scholar 

  54. Oh YJ, Francis JW, Markelonis GJ, Oh TH. Interleukin-1-beta and tumor necrosis factor-alpha increase peripheral-type benzodiazepine binding sites in cultured polygonal astrocytes. J Neurochem. 1992;58(6):2131–8.

    Article  PubMed  CAS  Google Scholar 

  55. Guo LM, Liu JY, Xu DZ, Li BS, Han H, Wang LH, et al. Application of molecular adsorbents recirculating system to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome. Liver Int. 2003;23 Suppl 3:16–20.

    Article  PubMed  CAS  Google Scholar 

  56. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071–81.

    Article  PubMed  CAS  Google Scholar 

  57. Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology. 2004;39(5):1441–9.

    Article  PubMed  Google Scholar 

  58. Jalan R, Olde Damink SW, Deutz NE, Davies NA, Garden OJ, Madhavan KK, et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation. 2003;75:2034–9.

    Article  PubMed  Google Scholar 

  59. Vaquero J, Butterworth RF. Mild hypothermia for the treatment of acute liver failure—what are we waiting for? Nat Clin Pract Gastroenterol Hepatol. 2007;4:528–9.

    Article  PubMed  Google Scholar 

  60. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, et al. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation. 2008;5:15.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Neuroscience Research Unit, Hôpital Saint-Luc (CHUM), 1058 St. Denis, Montreal, QC, Canada, H2X 3J4

    Roger F. Butterworth PhD, DSc

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  1. Roger F. Butterworth PhD, DSc
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Correspondence to Roger F. Butterworth PhD, DSc .

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  1. , Division of Gastroenterology, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, 44145, USA

    Kevin D. Mullen

  2. , Division of Gastroenterology, MetroHealth Medical Center, 2500 MetroHealth Medical Center, Cleveland, 44145, USA

    Ravi K. Prakash

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Butterworth, R.F. (2012). Neuroinflammation in the Pathogenesis of Hepatic Encephalopathy. In: Mullen, K., Prakash, R. (eds) Hepatic Encephalopathy. Clinical Gastroenterology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-836-8_3

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  • DOI: https://doi.org/10.1007/978-1-61779-836-8_3

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