Neurobiology of liver diseases

Česká verze

Authors: B. Mravec ^1,2; M. Szántová ³
Authors place of work: Fyziologický ústav, LF UK, Bratislava ¹; Biomedicínske centrum, Ústav experimentálnej endokrinológie, SAV, Bratislava ²; III. interná klinika LF UK a UN, Nemocnica akademika Ladislava Dérera, Bratislava ³
Published in the journal: Gastroent Hepatol 2023; 77(2): 103-11
Category: Hepatologie: přehledová práce
doi: https://doi.org/10.48095/ccgh2023103

Summary

The nervous system is an important factor that participates in the adaptive and compensatory reactions of the body, not only in physiological but also in pathological processes. Alterations in the activity of the nervous system may contribute to the development of somatic diseases and may also influence their progression. Experimental and clinical studies have shown that the nervous system also plays a role in liver diseases. Depending on the disease and on the mechanisms and pathways, the nervous system can play a positive as well as a negative role in liver diseases. The aim of this review is to describe the mechanisms and pathways through which the nervous system affects the development and progression of the most common liver diseases, such as alcoholic liver damage, non-alcoholic fatty liver disease, cholestatic liver diseases, hepatitis, cirrhosis, and hepatocellular carcinoma. In addition, we also describe the possible therapeutic consequences based on the modulation of signal transmission between the nervous system and the liver.

Keywords:

autonomic nervous system – Cirrhosis – Chronic hepatitis – hepatocellular carcinoma – alcoholic liver damage – cholestatic liver diseases – neurobiology – fatty liver disease

Zdroje

1. Boilly B, Faulkner S, Jobling P et al. Nerve Dependence: From Regeneration to Cancer. Cancer Cell 2017; 31 (3): 342–354. doi: 10.1016/j.ccell.2017.02.005.

2. Jensen KJ, Alpini G, Glaser S. Hepatic nervous system and neurobiology of the liver. Compr Physiol 2013; 3 (2): 655–665. doi: 10.1002/cphy.c120018.

3. Lipták P, Ďuríček M, Prokopič M et al. Autonómna dysregulácia pri syndróme dráždivého čreva, funkčnej dyspepsii a globus pharyngeus – prehľad literatúry a pilotné výsledky. Gastroent Hepatol 2020; 74 (4): 327–333. doi: 10.14735/amgh2020327.

4. NCZI: 2018 Zdravotnícka ročenka SR, NCZI, Bratislava, 2019, 227 s. ISBN: 978-80-89292-71-4.

5. NCZI: 2019 Zdravotnícka ročenka SR, NCZI, Bratislava, 2021, 248 s. ISBN: 978-80-89292-77-6.

6. NCZI: 2020 Zdravotnícka ročenka SR, NCZI, Bratislava, 2021, 260 s. ISBN: 978-80-89282-80-6. doi:

7. Collaborators GBDC. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2020; 5 (3): 245–266. doi: 10.1016/S2468-1253 (19) 30349-8.

8. Miller BM, Oderberg IM, Goessling W. Hepatic Nervous System in Development, Regeneration, and Disease. Hepatology 2021; 74 (6): 3513–3522. doi: 10.1002/hep.32055.

9. Yi CX, la Fleur SE, Fliers E et al. The role of the autonomic nervous liver innervation in the control of energy metabolism. Biochim Biophys Acta 2010; 1802 (4): 416–431. doi: 10.1016/ j.bbadis.2010.01.006.

10. Lelou E, Corlu A, Nesseler N et al. The Role of Catecholamines in Pathophysiological Liver Processes. Cells 2022; 11 (6): doi: 10.3390/cells11061021.

11. Murugan S, Boyadjieva N, Sarkar DK. Protective effects of hypothalamic beta-endorphin neurons against alcohol-induced liver injuries and liver cancers in rat animal models. Alcohol Clin Exp Res 2014; 38 (12): 2988–2997. doi: 10.1111/acer.12580.

12. Ishay Y, Kolben Y, Kessler A et al. Role of circadian rhythm and autonomic nervous system in liver function: a hypothetical basis for improving the management of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2021; 321 (4): G400–G412. doi: 10.1152/ajpgi.00186.2021.

13. European Association for the Study of the L, European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64 (6): 1388–1402. doi: 10.1016/j.jhep.2015.11.004.

14. Rebelos E, Iozzo P, Guzzardi MA et al. Brain-gut-liver interactions across the spectrum of insulin resistance in metabolic fatty liver disease. World J Gastroenterol 2021; 27 (30): 4999–5018. doi: 10.3748/wjg.v27.i30.4999.

15. Münzberg H, Qualls-Creekmore E, Berthoud HR et al. Neural Control of Energy Expenditure. Handb Exp Pharmacol 2016; 233: 173–194. doi: 10.1007/164_2015_33.

16. Guarino D, Nannipieri M, Iervasi G et al. The Role of the Autonomic Nervous System in the Pathophysiology of Obesity. Front Physiol 2017; 8: 665. doi: 10.3389/fphys.2017.00665.

17. Newton JL, Pairman J, Wilton K et al. Fatigue and autonomic dysfunction in non-alcoholic fatty liver disease. Clin Auton Res 2009; 19 (6): 319–326. doi: 10.1007/s10286-009-0031-4.

18. Sun W, Zhang D, Sun J et al. Association between non-alcoholic fatty liver disease and autonomic dysfunction in a Chinese population. QJM 2015; 108 (8): 617–624. doi: 10.1093/qjmed/hcv006.

19. Hurr C, Simonyan H, Morgan DA et al. Liver sympathetic denervation reverses obesity-induced hepatic steatosis. J Physiol 2019; 597 (17): 4565–4580. doi: 10.1113/JP277994.

20. Liu K, Yang L, Wang G et al. Metabolic stress drives sympathetic neuropathy within the liver. Cell Metab 2021; 33 (3): 666–675. doi: 10.1016/ j.cmet.2021.01.012.

21. Grant WF, Nicol LE, Thorn SR et al. Perinatal exposure to a high-fat diet is associated with reduced hepatic sympathetic innervation in one-year old male Japanese macaques. PLoS One 2012; 7 (10): e48119. doi: 10.1371/journal.pone.0048119.

22. Satapathy SK, Ochani M, Dancho M et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med 2011; 17 (7–8): 599–606. doi: 10.2119/molmed.2011.00083.

23. Nishio T, Taura K, Iwaisako K et al. Hepatic vagus nerve regulates Kupffer cell activation via alpha7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis. J Gastroenterol 2017; 52 (8): 965–976. doi: 10.1007/s00535-016-1304-z.

24. Szántová M. Podporné faktory v liečbe chronických hepatitíd. Trendy v hepatológii 2010; 3: 25–29. doi:

25. Mizuno K, Haga H, Okumoto K et al. Intrahepatic distribution of nerve fibers and alterations due to fibrosis in diseased liver. PLoS One 2021; 16 (4): e0249556. doi: 10.1371/journal.pone.0249556.

26. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006; 6 (4): 318–328. doi: 10.1038/nri1810.

27. Reardon C, Murray K, Lomax AE. Neuroimmune Communication in Health and Disease. Physiol Rev 2018; 98 (4): 2287–2316. doi: 10.1152/physrev.00035.2017.

28. Neuhuber WL, Tiegs G. Innervation of immune cells: evidence for neuroimmunomodulation in the liver. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (1): 884–892. doi: 10.1002/ar.a.20093.

29. Huang CC, Wu KL, Liu JS et al. Autonomic impairment in treatment-naive patients with chronic hepatitis B and C infections. Auton Neurosci 2021; 238: 102928. doi: 10.1016/j.autneu.2021.102928.

30. Poliwczak AR, Bialkowska J, Wozny J et al. Cardiovascular risk assessment by electrocardiographic Holter monitoring in patients with chronic hepatitis C. Arch Med Sci 2020; 16 (5): 1031–1039. doi: 10.5114/aoms.2020.96600.

31. Vere CC, Streba CT, Streba LM et al. Psychosocial stress and liver disease status. World J Gastroenterol 2009; 15 (24): 2980–2986. doi: 10.3748/wjg.15.2980.

32. Chida Y, Sudo N, Kubo C. Does stress exacerbate liver diseases? J Gastroenterol Hepatol 2006; 21 (1 Pt 2): 202–208. doi: 10.1111/j.14 40-1746.2006.04110.x.

33. Marsland AL, Bachen EA, Cohen S et al. Stress, immune reactivity and susceptibility to infectious disease. Physiol Behav 2002; 77 (4–5): 711–716. doi: 10.1016/s0031-9384 (02) 00923-x.

34. Burns VE, Ring C, Drayson M et al. Cortisol and cardiovascular reactions to mental stress and antibody status following hepatitis B vaccination: a preliminary study. Psychophysiology 2002; 39 (3): 361–368. doi: 10.1017/s00 48577201393022.

35. Balemba OB, Salter MJ, Mawe GM. Innervation of the extrahepatic biliary tract. Anat Rec A Discov Mol Cell Evol Biol 2004; 280 (1): 836–847. doi: 10.1002/ar.a.20089.

36. Ehrlich L, Scrushy M, Meng F et al. Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease. Clin Res Hepatol Gastroenterol 2018; 42 (4): 296–305. doi: 10.1016/ j.clinre.2018.03.009.

37. Yang H, Yang H, Wang L et al. Transcutaneous Neuromodulation improved inflammation and sympathovagal ratio in patients with primary biliary ssscholangitis and inadequate response to Ursodeoxycholic acid: a pilot study. BMC Complement Med Ther 2020; 20 (1): 242. doi: 10.1186/s12906-020-03036-w.

38. Dyson JK, Elsharkawy AM, Lamb CA et al. Fatigue in primary sclerosing cholangitis is associated with sympathetic over-activity and increased cardiac output. Liver Int 2015; 35 (5): 1633–1641. doi: 10.1111/liv.12709.

39. Amir M, Yu M, He P et al. Hepatic Autonomic Nervous System and Neurotrophic Factors Regulate the Pathogenesis and Progression of Non-alcoholic Fatty Liver Disease. Front Med (Lausanne) 2020; 7: 62. doi: 10.3389/fmed.2020. 00062.

40. Henriksen JH, Ring-Larsen H, Christensen NJ. Aspects of sympathetic nervous system regulation in patients with cirrhosis: a 10-year experience. Clin Physiol 1991; 11 (4): 293–306. doi: 10.1111/j.1475-097x.1991.tb00658.x.

41. Henriksen JH, Ring-Larsen H, Christensen NJ. Sympathetic nervous activity in cirrhosis. A survey of plasma catecholamine studies. J Hepatol 1985; 1 (1): 55–65. doi: 10.1016/s0168-8278 (85) 80068-4.

42. Estrela HF, Damasio ES, Fonseca EK et al. Differential Sympathetic Vasomotor Activation Induced by Liver Cirrhosis in Rats. PLoS One 2016; 11 (4): e0152512. doi: 10.1371/journal.pone.0152512.

43. Hendrickse MT, Triger DR. Vagal dysfunction and impaired urinary sodium and water excretion in cirrhosis. Am J Gastroenterol 1994; 89 (5): 750–757.

44. Mravec B. Neurobiology of cancer: Definition, historical overview, and clinical implications. Cancer Med 2022; 11 (4): 903–921. doi: 10.1002/cam4.4488.

45. Huan HB, Wen XD, Chen XJ et al. Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells. Brain Behav Immun 2017; 59: 118–134. doi: 10.1016/j.bbi.2016.08.016.

46. Li J, Yang XM, Wang YH et al. Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling. J Hepatol 2014; 60 (6): 1225–1234. doi: 10.1016/j.jhep.2014.02.025.

47. Adamcová Selčanová S, Takáč R, Vnenčáková J et al. Cirhóza pečene u rómskych pacientov z pohľadu hepatologického transplantačného centra. Gastroent Hepatol 2022; 76 (4): 334–340. doi: 10.48095/ccgh2022334.

48. Kjaer M, Jurlander J, Keiding S et al. No reinnervation of hepatic sympathetic nerves after liver transplantation in human subjects. J Hepatol 1994; 20 (1): 97–100. doi: 10.1016/s0168-8278 (05) 80473-8.

49. Ferreira LG, Santos LF, Anastacio LR et al. Resting energy expenditure, body composition, and dietary intake: a longitudinal study before and after liver transplantation. Transplantation 2013; 96 (6): 579–585. doi: 10.1097/TP.0b013e31829d924e.

50. Kim E, Choi DL, Jung JY et al. Shift in Sympathovagal Balance Toward Parasympathetic Predominance Is Associated With Attenuation of Portal Hyperperfusion in Cirrhotic Recipients Undergoing Living Donor Liver Transplant. Transplant Proc 2019; 51 (5): 1511–1515. doi: 10.1016/j.transproceed.2019.01.117.

51. Hirao H, Nakamura K, Kupiec-Weglinski JW. Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol 2022; 19 (4): 239–256. doi: 10.1038/s41575-021-00549-8.

52. Inoue T, Abe C, Kohro T et al. Non-canonical cholinergic anti-inflammatory pathway-mediated activation of peritoneal macrophages induces Hes1 and blocks ischemia/reperfusion injury in the kidney. Kidney Int 2019; 95 (3): 563–576. doi: 10.1016/j.kint.2018.09.020.

53. Buchholz B, Kelly J, Munoz M et al. Vagal stimulation mimics preconditioning and postconditioning of ischemic myocardium in mice by activating different protection mechanisms. Am J Physiol Heart Circ Physiol 2018; 314 (6): H1289–H1297. doi: 10.1152/ajpheart.00286.2017.

54. Tarras SL, Diebel LN, Liberati DM et al. Pharmacologic stimulation of the nicotinic anti-inflammatory pathway modulates gut and lung injury after hypoxia-reoxygenation injury. Surgery 2013; 154 (4): 841–847. doi: 10.1016/j.surg.2013.07.018.

55. Geng Y, Chen D, Zhou J et al. Role of Cholinergic Anti-Inflammatory Pathway in Treatment of Intestinal Ischemia-Reperfusion Injury by Electroacupuncture at Zusanli. Evid Based Complement Alternat Med 2017; 2017: 6471984. doi: 10.1155/2017/6471984.

56. Chies AB, Nakazato PCG, Spadella MA et al. Rivastigmine prevents injury induced by ischemia and reperfusion in rat liver. Acta Cir Bras 2018; 33 (9): 775–784. doi: 10.1590/s0102-86502 0180090000005.

57. Park J, Kang JW, Lee SM. Activation of the cholinergic anti-inflammatory pathway by nicotine attenuates hepatic ischemia/reperfusion injury via heme oxygenase-1 induction. Eur J Pharmacol 2013; 707 (1–3): 61–70. doi: 10.1016/j.ejphar.2013.03.026.

58. Bundzikova J, Pirnik Z, Lackovicova L et al. Brain-liver interactions during liver ischemia reperfusion injury: a minireview. Endocr Regul 2011; 45 (3): 163–172. doi: 10.4149/endo_2011_03_163.

59. Friman S, Wallin M, Gustafsson BI et al. Sympathetic nerves do not affect experimental ischemia-reperfusion injury of rat liver. Transplant Proc 2009; 41 (2): 743–745. doi: 10.1016/j.transproceed.2009.01.035.

60. Corruble E, Barry C, Varescon I et al. Depressive symptoms predict long-term mortality after liver transplantation. J Psychosom Res 2011; 71 (1): 32–37. doi: 10.1016/j.jpsychores.2010.12.008.

61. Rogal S, Shenai N, Kruckenberg K et al. Post-transplant Outcomes of Persons Receiving a Liver Graft for Alcoholic Liver Disease. Alcohol Alcohol 2018; 53 (2): 157–165. doi: 10.1093/alcalc/agx100.

62. Lombardi F, Malliani A, Pagani M et al. Heart rate variability and its sympatho-vagal modulation. Cardiovasc Res 1996; 32 (2): 208–216. doi: 10.1016/0008-6363 (96) 00116-2.

63. Abid NU, Mani AR. The mechanistic and prognostic implications of heart rate variability analysis in patients with cirrhosis. Physiol Rep 2022; 10 (8): e15261. doi: 10.14814/phy2.15261.

64. Ramadi KB, Srinivasan SS, Traverso G. Electroceuticals in the Gastrointestinal Tract. Trends Pharmacol Sci 2020; 41 (12): 960–976. doi: 10.1016/j.tips.2020.09.014.