Volume : 12, Issue : 09, September – 2025
Title:
MECHANISTIC PERSPECTIVES ON HEPATIC ENCEPHALOPATHY: THE IMPACT OF AMMONIA ACCUMULATION, NEUROINFLAMMATION AND ASTROCYTE DYSFUNCTION”
Authors :
Abhaya S A, Dr. John D Milton, Dr. Merlin N J, Dr. Shaiju S Dharan
Abstract :
Hepatic encephalopathy (HE), a neuropsychiatric disorder mainly caused by liver failure, leading to impaired detoxification of toxins like ammonia. Elevated ammonia crosses the blood-brain barrier, causing astrocyte swelling, brain edema, and disrupted neurotransmission, which impair neuronal function. Disease progression is also driven by oxidative stress, neuroinflammation, and mitochondrial dysfunction that damage neural cells and impair energy production. Experimental models have helped identify key pathogenic pathways and potential treatments, including antioxidants and strategies to preserve mitochondrial health. Central to HE are disturbances in neurotransmitters such as glutamate and GABA, along with activation of microglia and astrocytes that amplify inflammation and neural injury. Astrocyte swelling due to excess glutamine from ammonia detoxification contributes to brain edema and neurological symptoms. Early diagnosis and a comprehensive approach targeting ammonia reduction, neuroprotection, and inflammation are essential, with ongoing research providing optimism for the development of better treatments to enhance patient results.
Keywords: Hepatic Encephalopathy, Ammonia, Glutamate, Neuroinflammation, Oxidative Stress
Cite This Article:
Please cite this article in press Abhaya S A et al., Mechanistic Perspectives On Hepatic Encephalopathy: The Impact Of Ammonia Accumulation, Neuroinflammation And Astrocyte Dysfunction, Indo Am. J. P. Sci, 2025; 12(09).
REFERENCES:
1. Sandip Tejpal, Saajan Kumar Sharma. A comprehensive review on Hepatic encephalopathy: Pathophysiology, Symptoms, Epidemology, Classification, Diagnosis and Treatment. J. Res. Appl. Sci. Biotechnol.2024;3(4):170-80.
2. A.G Al-Hadad, A.M Al-Saidya. Development of an experimental hepatic encephalopathy in a rabbit model: Biochemical and immunohistochemical study. Iraqi Journal of Veterinary Sciences. 2022;36(1): 179-85.
3. A.G Al-Hadad, A.M Al-Saidya. Development of an experimental hepatic encephalopathy in a rabbit model: Biochemical and immunohistochemical study. Iraqi Journal of Veterinary Sciences. 2022;36(1): 179-85.
4. wounter claeys, Lien Van Hoecks, Sander Lefere, Anja Geerts, Xavier Verhelst. Review The neuroglia vascular unit in hepatic encephalopathy. Jhep Reports. 2021;3(5):1-5.
5. M.M. Said, A.M. Medhat. Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF κB/IL-6 and Nrf2/HO-1 signalling pathways. j.bioorg. 2020;1(1):1-31.
6. Alabsawy E, Shalimar MF, Sheikh MP, Ballester SK, Acharya BA, Jalan R (2022) Overt hepatic encephalopathy is an independent risk factor for de novo infection in cirrhotic patients with acute decompensation. Aliment Pharmacol Ther 55(6):722–732
7. Jose Biller and Jose M. Ferro. Neurologic Aspects of Systemic Disease Part II. Handbook of Clinical Neurology 2014;120 (3):661-74.
8. Moro, A. Pathophysiology and management of hepatic encephalopathy. Nature Reviews Gastroenterology & Hepatology. 2022;19(4): 222-34.
9. Farjam, M., Dehdab, P., Abbassnia, F., Mehrabani, D., Tanideh, N., Pakbaz, S., & Imanieh,
M. H. (2012). Thioacetamide-induced acute hepatic encephalopathy in rat: behavioral, biochemical and histological changes. Iranian Red Crescent medical journal, 14(3), 164–170.
10. Butterworth RF. Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology. 2011;53:1372–6.
11. Bismuth M, Funakoshi N, Cadranel JF, Blanc P. Hepatic encephalopathy: from pathophysiology to therapeutic management. Eur J Gastroenterol Hepatol. 2011;23:8–22.
12. Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol. 2011;7:222–33.
13. Bruck R, Weiss S, Traister A, Zvibel I, Aeed H, Halpern Z, Oren R. Induced hypothyroidism accelerates the regression of liver fibrosis in rats. J Gastroenterol Hepatol. 2007;22:2189–94.
14. Wang WW, Zhang Y, Huang XB, You N, Zheng L, Li J. Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction. World Journal of Gastroenterology. 2017;23(38):6983.
15. Tomiga Y, Tanaka K, Kusuyama J, Takano A, Higaki Y, Anzai K, Takahashi H. Exercise training ameliorates carbon tetrachloride-induced liver fibrosis and anxiety-like behaviors. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2024;327(6):850-60.
16. Llansola M, Arenas YM, Sancho-Alonso M, Mincheva G, Palomares-Rodriguez A, Doverskog M, Izquierdo-Altarejos P, Felipo V. Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications. Frontiers in Pharmacology. 2024;15(1):1358323.
17. Kroupina K, Bémeur C, Rose CF. Amino acids, ammonia, and hepatic encephalopathy. Analytical biochemistry. 2022;649(1):114696.
18. Huang J, Gong Z, Kong Y, Huang Y, Wang H, Kang Y, Zhan S. Electroacupuncture Synergistically Inhibits Proinflammatory Cytokine Production and Improves Cognitive Function in Rats with Cognitive Impairment due to Hepatic Encephalopathy through p38MAPK/STAT3 and TLR4/NF-κB Signaling Pathways. Evid Based Complement Alternat Med. 2021;1(1): 7992688.
19. Santos RPC, Toscano ECB, Rachid MA. Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies. Arq Neuropsiquiatr. 2023;81(7):656-69.
20. Al Shaima G. Abd El Salam, Nesma A. Abd Elrazik. Cinnamaldehyde/lactulose combination therapy alleviates thioacetamide-induced hepatic encephalopathy via targeting P2X7R-mediated NLRP3 inflammasome signaling. Life Sciences. 2024;344(1):1-10.
21. A.R. Jayakumar, M.D. Norenberg, Hyperammonemia in hepatic encephalopathy, J. Clin. Exp. Hepatol. 8 (3) (2018) 272–280.
22. Abdelrahman, R. S, Abdelaziz R. R., Abdelmageed, M. E. Montelukast alleviates thioacetamide-induced hepatic encephalopathy in rats. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2025;1(1):1-2.
23. Gallego-Durán R, Hadjihambi A, Ampuero J, Rose CF, Jalan R, Romero-Gómez M. Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2024 Nov;21(11):774-791.
24. Haussinger, D. Nitrogen metabolism in liver: structural and functional organization and physiological relevance. Biochem. J. 267, 281–290 (1990).
25. European Association for the Study of the Liver EASL Clinical Practice Guidelines on the management of hepatic encephalopathy. J. Hepatol. 77, 807–824 (2022).
26. Wang, W., Lu, H., Lu, X. et al. Effect of tumor necrosis factor-α on the expression of the ammonia transporter Rhcg in the brain in mice with acute liver failure. J Neuroinflammation.2018;15(234):1-4.
27. Rama Rao, K V Jayakumar, Arumugam R, Norenberga,M D. Glutamine in the pathogensis of acute hepatic encephalopathy. Neurochemistry International. 2012;61(4):575-80.
28. Fogel WA, Andrzejewski W, Maśliński C. Neurotransmitters in hepatic encephalopathy. Acta Neurobiol Exp (Wars). 1990;50(4-5):281-93.
29. Chan, H., Hazell, A.S., Desjardins, P., and Butterworth, R.F. (2000). Effects of ammonia on glutamate transporter (GLAST) protein and mRNA in cultured rat cortical astrocytes. Neurochem. Int. 37:243–248.
30. Butterworth, R.F. Neurotransmitter Dysfunction in Hepatic Encephalopathy: New Approaches and New Findings. Metab Brain Dis 2001;16:55–65.
31. Weissenborn K. Hepatic encephalopathy: definition, clinical grading and diagnostic principles. Drugs . 2019;79:5–9.
32. Albrecht J, Dolińska M. Glutamine as a pathogenic factor in hepatic encephalopathy. J Neurosci Res. 2001 Jul 1;65(1):1-5.
33. Romero-Gomez M, Jover M, Diaz-Gomez D, de Teran LC, Rodrigo R, Camacho I, Echevarria M, Felipo V, Bautista JD. World J Gastroenterol. 2006;12(15):2406-11
34. Romero-Gómez M. Role of phosphate-activated glutaminase in the pathogenesis of hepatic encephalopathy. Metab Brain Dis. 2005 Dec;20(4):319-25.
35. El-Marasy SA, El Awdan SA, Abd-Elsalam RM. Protective role of chrysin on thioacetamide-induced hepatic encephalopathy in rats. Chem Biol Interact. 2019;299:111-119.
36. A. Ahad, A.A. Ganai, M. Mujeeb, W.A. Siddiqui, Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats, Toxicol. Appl. Pharmacol. 2014;279:61-7.
37. C. Anbarasu, B. Rajkapoor, K.S. Bhat, J. Giridharan, A.A. Amuthan, K. Satish, Protective 16 effect of Pisonia aculeata on thioacetamide induced hepatotoxicity in rats, Asian Pac. J. Trop. Biomed. 2012;2:511-515.
38. Maria Eduarda Rocha, Renata Kelly Luna, Wilma Helena Oliveira, Eduardo Duarte-Silva. Tadalafil restores long-term memory and synaptic plasticity in mice with hepatic encephalopathy. Toxicology and Applied Pharmacology. 2019;379(1):1-3.
39. S. Erceg et al. Role of extracellular cGMP and of hyperammonemia in the impairment of learning in rats with chronic hepatic failure. Therapeutic implications. Neurochem. Int. 2006;48(6):441-6.
40. Fabiana G, Elisa N, Carollina D R, Fernanda F. Hyperammonemia compromises glutamate metabolism and reduces BDNF in the rat hippocampus. Neurotoxicology.2017;62(1):46-55.
41. Anthony O. Ahmed, Andrew M. Mantini, Daniel J. Fridberg, Peter F. Buckley. Brain- derived neurotrophic factor (BDNF) and neurocognitive deficits in people with schizophrenia: A meta-analysis. Psychiatry Research. 226(1):1-13.
42. Westenberger, G., Sellers, J., Fernando, S., Junkins, S., Han, S. M., Min, K., & Lawan, A. (2021). Function of Mitogen-Activated Protein Kinases in Hepatic Inflammation. Journal of cellular signaling, 2(3), 172–180.
43. Shambhu Kumar Prasad, Arup Acharjee, Vishal Vikram Singh, Surendra Kumar Trigun, Papia Acharjee. Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction. Metabolic Brain Disease. 2024; 39(8): 1649-65.
44. Alexander B, Aslam M, Benjamin IS (1999) An investigation of the relationship between the liver and brain using an isolated perfused rat brain preparation. J Pharmacol Toxicol Methods 42:31–37.
45. imicic D, Cudalbu C, Pierzchala K. Overview of oxidative stress findings in hepatic encephalopathy: From cellular and ammonium-based animal models to human data. Anal Biochem. 2022;654:114795.
46. Bai, Y., Li, K., Li, X. et al. Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice. Nat Commun. 2023;14:4456.
47. Gorg, B. et al. O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia- induced oxidative stress and senescence in hepatic encephalopathy. J. Hepatol. 2019;71:930– 941.
48. Le Guennec L, Mouri S, Thabut D, Weiss N. Blood-brain barrier dysfunction in hepatic encephalopathy: pathophysiology, diagnostic assessment and therapeutic perspectives. Metab Brain Dis. 2025;40(5):223.
49. Enas S Gad, Sara A Aldossary, Mona R. El-Ansary. Cilostazol counteracts mitochondrial dysfunction in hepatic encephalopathy rat model: Insights into the role of Camp/ AMPK/S1RT1/PINK-1/ parkin hub and p-CREB/ BDNF/ TrkB neuroprotective trajectory. European Journal of Pharmacology. 2025;987(1):1-23.
50. Sepehrinezhad A, Zarifkar A, Namvar G, Shahbazi A, Williams R. Astrocyte swelling in hepatic encephalopathy: molecular perspective of cytotoxic edema. Metab Brain Dis. 2020 Apr;35(4):559-578.
51. Wouter Claeys, Anja Geerts, Lien Van Hoecke, Christophe Van Steenkiste, Roosmarijn E Vandenbroucke. Role of astrocytes and microglia in hepatic encephalopathy associated with advanced chronic liver disease: lessons from animal studies. Neural Regen Res. 2025;20(12):3461-75.
52. Reddy PV, Rama Rao KV, Norenberg MD. Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes. J Neurosci Res. 2009;87(12):2677-85.
53. Lachmann V, Görg B, Bidmon HJ, Keitel V, Häussinger D. Precipitants of hepatic encephalopathy induce rapid astrocyte swelling in an oxidative stress dependent manner. Arch Biochem Biophys. 2013;536(2):143-51.
54. Jayakumar AR, Tong XY, Curtis KM, Ruiz-Cordero R, Abreu MT, Norenberg MD. Increased toll-like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy. J Neurochem. 2014;128(6):890-903.
55. ayakumar AR, Tong XY, Curtis KM, Ruiz-Cordero R, Shamaladevi N, Abuzamel M, Johnstone J, Gaidosh G, Rama Rao KV, Norenberg MD. Decreased astrocytic thrombospondin- 1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies. J Neurochem. 2014;131(3):333-47.
56. Natália Ferreira Mendes, Flora França Nogueira Mariotti, José Simões de Andrade, Milena de Barros Viana, Isabel Cristina Céspedes. Lactulose decreases neuronal activation and attenuates motor behavioral deficits in hyperammonemic rats. Metab Brain Dis. 2017; 32(6)2073-83.
57. Weber FL Jr. Lactulose and combination therapy of hepatic encephalopathy: the role of the intestinal microflora. Dig Dis. 1996;14 Suppl 1:53-63.
58. Uribe-E M, Moran S, Poo JL, Munoz RM. In vitro and in vivo lactose and lactulose effects on colonic fermentation and portal-systemic encephalopathy parameters. Scand J Gastroenterol Suppl. 1997; 222:49-52.
59. Abdelrahman RS, Abdelaziz RR, Abdelmageed ME. Montelukast alleviates thioacetamide-induced hepatic encephalopathy in rats. Naunyn Schmiedebergs Arch Pharmacol. 2025;1(1):1-12.
60. Hosam Alazazzi, Ahmed T Algahiny, Zain Sharif, Niloy Sil, Yasir A Zaidi. Evaluating Clinical Outcomes of Adjunct Rifaximin Therapy in Patients with Overt Hepatic Encephalopathy: A Prospective Randomized Study.2025; 15(1):58-62.
61. Toris GT, Bikis C, Tsourouflis G, et al. Hepatic encephalopathy: An updated approach from pathogenesis to treatment. Med Sci Monit. 2011;17(2):53–63.