Exploring the Complexities of Hepatic Encephalopathy: Pathophysiology and Innovative Therapeutic Options
DOI:
https://doi.org/10.56782/pps.402Keywords:
Hyperammonemia, Hepatic Encephalopathy, Vagus Nerve, Blood-Brain Barrier, Neuroinflammation, CirrhosisAbstract
Hepatic encephalopathy is a significant neuropsychiatric complication associated with liver disease, marked by cognitive impairment and changes in mental status. The review discusses the multicomponent pathophysiological mechanisms of disease, focusing on the fundamental role of the gut-brain axis. Recent advances have defined critical contributory elements such as the accumulation of ammonia, neuroinflammation, neurotransmitter imbalance, and microbiome dysregulation. Moreover, understanding the impact of gut microbiota on brain function is essential for developing targeted interventions. Modern treatment strategies have been expanded to include gut-directed therapies, metabolic manipulation, novel molecular therapeutics, new drug delivery systems, and precision medicine significantly improving treatment outcomes. In contrast, artificial intelligence applications revolutionized patient monitoring and therapeutic strategies. These technological advancements have also facilitated personalized approaches to treatment. Furthermore, ongoing research into biomarkers is crucial for early diagnosis and monitoring of disease progression. The identification of specific biomarkers can enhance our understanding of disease severity and guide therapeutic decisions. These advances have improved knowledge of inter-organ system interaction and biomarker-based strategies that have improved the outcomes in these patients and opened new vistas for future therapeutic strategies. Ultimately, a comprehensive approach that integrates these findings will be essential for the effective management and treatment of hepatic encephalopathy.
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[1] H. Vilstrup et al., “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, vol. 60, no. 2, pp. 715–735, Aug. 2014, doi: 10.1002/hep.27210. DOI: https://doi.org/10.1002/hep.27210
[2] A. Mancini, F. Campagna, P. Amodio, and K. M. Tuohy, “Gut : liver : brain axis: the microbial challenge in the hepatic encephalopathy,” Food Funct, vol. 9, no. 3, pp. 1373–1388, 2018, doi: 10.1039/C7FO01528C.
[3] S. El Aidy, R. Stilling, T. G. Dinan, and J. F. Cryan, “Microbiome to Brain: Unravelling the Multidirectional Axes of Communication,” 2016, pp. 301–336. doi: 10.1007/978-3-319-20215-0_15. DOI: https://doi.org/10.1007/978-3-319-20215-0_15
[4] M. Kandpal et al., “Dysbiosis of Gut Microbiota from the Perspective of the Gut–Brain Axis: Role in the Provocation of Neurological Disorders,” Metabolites, vol. 12, no. 11, p. 1064, Nov. 2022, doi: 10.3390/metabo12111064. DOI: https://doi.org/10.3390/metabo12111064
[5] M. A. Ellul, S. A. Gholkar, and T. J. Cross, “Hepatic encephalopathy due to liver cirrhosis,” BMJ, p. h4187, Aug. 2015, doi: 10.1136/bmj.h4187. DOI: https://doi.org/10.1136/bmj.h4187
[6] N. M. Bass, “A Brief History of Hepatic Encephalopathy,” Clin Liver Dis (Hoboken), vol. 18, no. S1, pp. 49–62, Oct. 2021, doi: 10.1002/cld.1119. DOI: https://doi.org/10.1002/cld.1119
[7] R. K. Prakash and K. D. Mullen, “Hepatic Encephalopathy,” in Schiff’s Diseases of the Liver, Wiley, 2011, pp. 421–444. doi: 10.1002/9781119950509.ch18. DOI: https://doi.org/10.1002/9781119950509.ch18
[8] N. Dharel and J. S. Bajaj, “Definition and Nomenclature of Hepatic Encephalopathy,” J Clin Exp Hepatol, vol. 5, pp. S37–S41, Mar. 2015, doi: 10.1016/j.jceh.2014.10.001. DOI: https://doi.org/10.1016/j.jceh.2014.10.001
[9] S. L. Flamm, “Complications of Cirrhosis in Primary Care: Recognition and Management of Hepatic Encephalopathy,” Am J Med Sci, vol. 356, no. 3, pp. 296–303, Sep. 2018, doi: 10.1016/j.amjms.2018.06.008. DOI: https://doi.org/10.1016/j.amjms.2018.06.008
[10] H. KHOBRAGADE, T. MANOHAR, and A. SATHAWANE, “Precipitating Factors and Clinico-Endoscopic Study of Patients with Hepatic Encephalopathy Type C,” Journal of Contemporary Medicine, vol. 12, no. 4, pp. 559–564, Jul. 2022, doi: 10.16899/jcm.979964. DOI: https://doi.org/10.16899/jcm.979964
[11] H. M. Singh, L. Romesh Sharma, and M. Bijoy, “PRECIPITATING FACTORS AND OUTCOME OF HEPATIC ENCEPHALOPATHY-A HOSPITAL BASE CROSS SECTIONAL STUDY,” International Journal of Academic Medicine and Pharmacy, 2017, doi: 10.47009/jamp.2023.5.5.356.
[12] A. Jaffe, J. K. Lim, and S. S. Jakab, “Pathophysiology of Hepatic Encephalopathy,” Clin Liver Dis, vol. 24, no. 2, pp. 175–188, May 2020, doi: 10.1016/j.cld.2020.01.002. DOI: https://doi.org/10.1016/j.cld.2020.01.002
[13] K. Kroupina, C. Bémeur, and C. F. Rose, “Amino acids, ammonia, and hepatic encephalopathy,” Anal Biochem, vol. 649, p. 114696, Jul. 2022, doi: 10.1016/j.ab.2022.114696. DOI: https://doi.org/10.1016/j.ab.2022.114696
[14] D. R. Aldridge, E. J. Tranah, and D. L. Shawcross, “Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation,” J Clin Exp Hepatol, vol. 5, pp. S7–S20, Mar. 2015, doi: 10.1016/j.jceh.2014.06.004. DOI: https://doi.org/10.1016/j.jceh.2014.06.004
[15] S. Matsumoto, J. Häberle, J. Kido, H. Mitsubuchi, F. Endo, and K. Nakamura, “Urea cycle disorders—update,” J Hum Genet, vol. 64, no. 9, pp. 833–847, Sep. 2019, doi: 10.1038/s10038-019-0614-4. DOI: https://doi.org/10.1038/s10038-019-0614-4
[16] I. D. Limón, I. Angulo-Cruz, L. Sánchez-Abdon, and A. Patricio-Martínez, “Disturbance of the Glutamate-Glutamine Cycle, Secondary to Hepatic Damage, Compromises Memory Function,” Front Neurosci, vol. 15, Jan. 2021, doi: 10.3389/fnins.2021.578922. DOI: https://doi.org/10.3389/fnins.2021.578922
[17] S. Mahmoud, M. Gharagozloo, C. Simard, and D. Gris, “Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release,” Cells, vol. 8, no. 2, p. 184, Feb. 2019, doi: 10.3390/cells8020184. DOI: https://doi.org/10.3390/cells8020184
[18] P. R. Angelova, A. J. C. Kerbert, A. Habtesion, A. Hall, A. Y. Abramov, and R. Jalan, “Hyperammonaemia induces mitochondrial dysfunction and neuronal cell death,” JHEP Reports, vol. 4, no. 8, p. 100510, Aug. 2022, doi: 10.1016/j.jhepr.2022.100510. DOI: https://doi.org/10.1016/j.jhepr.2022.100510
[19] S. R. Archie, A. Al Shoyaib, and L. Cucullo, “Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview,” Pharmaceutics, vol. 13, no. 11, p. 1779, Oct. 2021, doi: 10.3390/pharmaceutics13111779.
[20] A. R. Jayakumar, K. V. Rama Rao, and M. D. Norenberg, “Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects,” J Clin Exp Hepatol, vol. 5, pp. S21–S28, Mar. 2015, doi: 10.1016/j.jceh.2014.07.006. DOI: https://doi.org/10.1016/j.jceh.2014.07.006
[21] A. Srivastava, S. K. Yadav, S. K. Yachha, M. A. Thomas, V. A. Saraswat, and R. K. Gupta, “Pro‐inflammatory cytokines are raised in extrahepatic portal venous obstruction, with minimal hepatic encephalopathy,” J Gastroenterol Hepatol, vol. 26, no. 6, pp. 979–986, Jun. 2011, doi: 10.1111/j.1440-1746.2011.06706.x. DOI: https://doi.org/10.1111/j.1440-1746.2011.06706.x
[22] V. Jaeger, S. DeMorrow, and M. McMillin, “The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy,” J Clin Transl Hepatol, vol. 7, no. X, pp. 1–10, Dec. 2019, doi: 10.14218/JCTH.2019.00025.
[23] W. M. Elzefzafy, A. Abou lEla, and M. H. Maabady, “Role of Tumor Necrosis Factor Alpha , Ghrelin , Evoked Potentials in Hepatic Encephalopathy,” Egypt J Hosp Med, vol. 53, pp. 846–854, Oct. 2013, doi: 10.12816/0001647. DOI: https://doi.org/10.12816/0001647
[24] C. Labenz et al., “Raised serum Interleukin‐6 identifies patients with liver cirrhosis at high risk for overt hepatic encephalopathy,” Aliment Pharmacol Ther, vol. 50, no. 10, pp. 1112–1119, Nov. 2019, doi: 10.1111/apt.15515. DOI: https://doi.org/10.1111/apt.15515
[25] M. Luo, L. Li, E. Yang, and W. Cao, “Relationship between interleukin‐6 and ammonia in patients with minimal hepatic encephalopathy due to liver cirrhosis,” Hepatology Research, vol. 42, no. 12, pp. 1202–1210, Dec. 2012, doi: 10.1111/j.1872-034X.2012.01047.x. DOI: https://doi.org/10.1111/j.1872-034X.2012.01047.x
[26] O. Cauli et al., “Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy,” Metab Brain Dis, vol. 24, no. 1, pp. 69–80, Mar. 2009, doi: 10.1007/s11011-008-9115-4. DOI: https://doi.org/10.1007/s11011-008-9115-4
[27] E. A. Jones, “Ammonia, the GABA Neurotransmitter System, and Hepatic Encephalopathy,” Metab Brain Dis, vol. 17, no. 4, pp. 275–281, 2002, doi: 10.1023/A:1021949616422. DOI: https://doi.org/10.1023/A:1021949616422
[28] A. Michalak, K. Knecht, and R. F. Butterworth, “Hepatic Encephalopathy in Acute Liver Failure: Role of the Glutamate System,” 1997, pp. 35–43. doi: 10.1007/978-1-4615-5945-0_2. DOI: https://doi.org/10.1007/978-1-4615-5945-0_2
[29] R. F. Butterworth, J. Lavoie, J.-F. Giguère, G. P. Layrargues, and M. Bergeron, “Cerebral GABA-ergic and glutamatergic function in hepatic encephalopathy,” Neurochem Pathol, vol. 6, no. 1–2, pp. 131–144, Feb. 1987, doi: 10.1007/BF02833603. DOI: https://doi.org/10.1007/BF02833603
[30] S. Dhanda and R. Sandhir, “Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy,” Behavioural Brain Research, vol. 286, pp. 222–235, Jun. 2015, doi: 10.1016/j.bbr.2015.01.042. DOI: https://doi.org/10.1016/j.bbr.2015.01.042
[31] R. F. Butterworth, L. Spahr, S. Fontaine, and G. P. Layrargues, “Manganese toxicity, dopaminergic dysfunction and hepatic encephalopathy,” Metab Brain Dis, vol. 10, no. 4, pp. 259–267, Dec. 1995, doi: 10.1007/BF02109357. DOI: https://doi.org/10.1007/BF02109357
[32] J. S. Bajaj, “The role of microbiota in hepatic encephalopathy,” Gut Microbes, vol. 5, no. 3, pp. 397–403, May 2014, doi: 10.4161/gmic.28684. DOI: https://doi.org/10.4161/gmic.28684
[33] R. Rai, V. A. Saraswat, and R. K. Dhiman, “Gut Microbiota: Its Role in Hepatic Encephalopathy,” J Clin Exp Hepatol, vol. 5, pp. S29–S36, Mar. 2015, doi: 10.1016/j.jceh.2014.12.003.
[34] S.-M. Won et al., “The Link between Gut Microbiota and Hepatic Encephalopathy,” Int J Mol Sci, vol. 23, no. 16, p. 8999, Aug. 2022, doi: 10.3390/ijms23168999.
[35] X. Yang, K. Qiu, Y. Jiang, Y. Huang, Y. Zhang, and Y. Liao, “Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms,” Int J Mol Sci, vol. 25, no. 14, p. 7621, Jul. 2024, doi: 10.3390/ijms25147621. DOI: https://doi.org/10.3390/ijms25147621
[36] M. Carabotti, A. Scirocco, M. A. Maselli, and C. Severi, “The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.,” Ann Gastroenterol, vol. 28, no. 2, pp. 203–209, 2015.
[37] G. Fernandes, “The Co-Relation Between The Nervous System And Gut Health,” 2023, doi: 10.9790/0853-2206102734.
[38] M. Yan et al., “Gut liver brain axis in diseases: the implications for therapeutic interventions,” Signal Transduct Target Ther, vol. 8, no. 1, p. 443, Dec. 2023, doi: 10.1038/s41392-023-01673-4.
[39] S. Qu et al., “Gut microbiota modulates neurotransmitter and gut-brain signaling,” Microbiol Res, vol. 287, p. 127858, Oct. 2024, doi: 10.1016/j.micres.2024.127858. DOI: https://doi.org/10.1016/j.micres.2024.127858
[40] H. H. Nguyen and M. G. Swain, “Avenues within the gut-liver-brain axis linking chronic liver disease and symptoms,” Front Neurosci, vol. 17, Jul. 2023, doi: 10.3389/fnins.2023.1171253. DOI: https://doi.org/10.3389/fnins.2023.1171253
[41] T. Sun, M. Feng, A. Manyande, H. Xiang, J. Xiong, and Z. He, “Regulation of mild cognitive impairment associated with liver disease by humoral factors derived from the gastrointestinal tract and MRI research progress: a literature review,” Front Neurosci, vol. 17, Jun. 2023, doi: 10.3389/fnins.2023.1206417.
[42] S. J. Gairing et al., “Evaluation of IL‐6 for Stepwise Diagnosis of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis,” Hepatol Commun, vol. 6, no. 5, pp. 1113–1122, May 2022, doi: 10.1002/hep4.1883. DOI: https://doi.org/10.1002/hep4.1883
[43] R. A. Hawkins, A. M. Mans, and J. F. Biebuyck, “Changes in brain metabolism in hepatic encephalopathy,” Neurochem Pathol, vol. 6, no. 1–2, pp. 35–66, Feb. 1987, doi: 10.1007/BF02833600. DOI: https://doi.org/10.1007/BF02833600
[44] N. Palomero-Gallagher and K. Zilles, “Neurotransmitter receptor alterations in hepatic encephalopathy: A review,” Arch Biochem Biophys, vol. 536, no. 2, pp. 109–121, Aug. 2013, doi: 10.1016/j.abb.2013.02.010. DOI: https://doi.org/10.1016/j.abb.2013.02.010
[45] Z. Chen et al., “The Role of Intestinal Bacteria and Gut–Brain Axis in Hepatic Encephalopathy,” Front Cell Infect Microbiol, vol. 10, Jan. 2021, doi: 10.3389/fcimb.2020.595759. DOI: https://doi.org/10.3389/fcimb.2020.595759
[46] P. P. Bloom, E. B. Tapper, V. B. Young, and A. S. Lok, “Microbiome therapeutics for hepatic encephalopathy,” J Hepatol, vol. 75, no. 6, pp. 1452–1464, Dec. 2021, doi: 10.1016/j.jhep.2021.08.004.
[47] C. Llorente and B. Schnabl, “The Gut Microbiota and Liver Disease,” Cell Mol Gastroenterol Hepatol, vol. 1, no. 3, pp. 275–284, May 2015, doi: 10.1016/j.jcmgh.2015.04.003. DOI: https://doi.org/10.1016/j.jcmgh.2015.04.003
[48] A. Rocco, C. Sgamato, D. Compare, P. Coccoli, O. M. Nardone, and G. Nardone, “Gut Microbes and Hepatic Encephalopathy: From the Old Concepts to New Perspectives,” Front Cell Dev Biol, vol. 9, Nov. 2021, doi: 10.3389/fcell.2021.748253. DOI: https://doi.org/10.3389/fcell.2021.748253
[49] R. Rai, V. A. Saraswat, and R. K. Dhiman, “Gut Microbiota: Its Role in Hepatic Encephalopathy,” J Clin Exp Hepatol, vol. 5, pp. S29–S36, Mar. 2015, doi: 10.1016/j.jceh.2014.12.003. DOI: https://doi.org/10.1016/j.jceh.2014.12.003
[50] J. Lachar and J. Bajaj, “Changes in the Microbiome in Cirrhosis and Relationship to Complications: Hepatic Encephalopathy, Spontaneous Bacterial Peritonitis, and Sepsis,” Semin Liver Dis, vol. 36, no. 04, pp. 327–330, Dec. 2016, doi: 10.1055/s-0036-1593881. DOI: https://doi.org/10.1055/s-0036-1593881
[51] M. Li et al., “Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS,” JHEP Reports, vol. 4, no. 5, p. 100448, May 2022, doi: 10.1016/j.jhepr.2022.100448. DOI: https://doi.org/10.1016/j.jhepr.2022.100448
[52] P. P. Bloom, E. B. Tapper, V. B. Young, and A. S. Lok, “Microbiome therapeutics for hepatic encephalopathy,” J Hepatol, vol. 75, no. 6, pp. 1452–1464, Dec. 2021, doi: 10.1016/j.jhep.2021.08.004. DOI: https://doi.org/10.1016/j.jhep.2021.08.004
[53] M. Madsen, N. Kimer, F. Bendtsen, and A. M. Petersen, “Fecal microbiota transplantation in hepatic encephalopathy: a systematic review,” Scand J Gastroenterol, vol. 56, no. 5, pp. 560–569, May 2021, doi: 10.1080/00365521.2021.1899277. DOI: https://doi.org/10.1080/00365521.2021.1899277
[54] A. A. Imani Fooladi, H. M. Hosseini, M. R. Nourani, S. Khani, and S. M. Alavian, “Probiotic as a Novel Treatment Strategy Against Liver Disease,” Hepat Mon, vol. 13, no. 2, Feb. 2013, doi: 10.5812/hepatmon.7521. DOI: https://doi.org/10.5812/hepatmon.7521
[55] J. Gao, R. Nie, H. Chang, W. Yang, and Q. Ren, “A meta-analysis of microbiome therapies for hepatic encephalopathy,” Eur J Gastroenterol Hepatol, vol. 35, no. 9, pp. 927–937, Sep. 2023, doi: 10.1097/MEG.0000000000002596. DOI: https://doi.org/10.1097/MEG.0000000000002596
[56] G. Bongaerts, R. Severijnen, and H. Timmerman, “Effect of antibiotics, prebiotics and probiotics in treatment for hepatic encephalopathy,” Med Hypotheses, vol. 64, no. 1, pp. 64–68, Jan. 2005, doi: 10.1016/j.mehy.2004.07.029. DOI: https://doi.org/10.1016/j.mehy.2004.07.029
[57] S.-M. Won et al., “The Link between Gut Microbiota and Hepatic Encephalopathy,” Int J Mol Sci, vol. 23, no. 16, p. 8999, Aug. 2022, doi: 10.3390/ijms23168999. DOI: https://doi.org/10.3390/ijms23168999
[58] M. Yan et al., “Gut liver brain axis in diseases: the implications for therapeutic interventions,” Signal Transduct Target Ther, vol. 8, no. 1, p. 443, Dec. 2023, doi: 10.1038/s41392-023-01673-4. DOI: https://doi.org/10.1038/s41392-023-01673-4
[59] C. F. Rose, “Ammonia-Lowering Strategies for the Treatment of Hepatic Encephalopathy,” Clin Pharmacol Ther, vol. 92, no. 3, pp. 321–331, Sep. 2012, doi: 10.1038/clpt.2012.112. DOI: https://doi.org/10.1038/clpt.2012.112
[60] S. Tejpal, S. K. Sharma, A. Sharma, and S. Sharma, “A Comprehensive Review on Hepatic Encephalopathy: Pathophysiology, Symptoms, Epidemiology, Classification, Diagnosis and Treatment,” Journal for Research in Applied Sciences and Biotechnology, vol. 3, no. 3, pp. 170–180, Jul. 2024, doi: 10.55544/jrasb.3.3.27. DOI: https://doi.org/10.55544/jrasb.3.3.27
[61] W. Yang, G. Guo, and C. Sun, “Therapeutic potential of rifaximin in liver diseases,” Biomedicine & Pharmacotherapy, vol. 178, p. 117283, Sep. 2024, doi: 10.1016/j.biopha.2024.117283. DOI: https://doi.org/10.1016/j.biopha.2024.117283
[62] G. T. Toris, C. N. Bikis, G. S. Tsourouflis, and S. E. Theocharis, “Hepatic encephalopathy: An updated approach from pathogenesis to treatment,” Medical Science Monitor, vol. 17, no. 2, pp. RA53–RA63, 2011, doi: 10.12659/MSM.881387. DOI: https://doi.org/10.12659/MSM.881387
[63] S. Colosimo, S. Bertoli, and F. Saffioti, “Use of Branched-Chain Amino Acids as a Potential Treatment for Improving Nutrition-Related Outcomes in Advanced Chronic Liver Disease,” Nutrients, vol. 15, no. 19, p. 4190, Sep. 2023, doi: 10.3390/nu15194190. DOI: https://doi.org/10.3390/nu15194190
[64] N. J. Hunt, D. Wahl, L. J. Westwood, G. P. Lockwood, D. G. Le Couteur, and V. C. Cogger, “Targeting the liver in dementia and cognitive impairment: Dietary macronutrients and diabetic therapeutics,” Adv Drug Deliv Rev, vol. 190, p. 114537, Nov. 2022, doi: 10.1016/j.addr.2022.114537. DOI: https://doi.org/10.1016/j.addr.2022.114537
[65] C. F. Rose et al., “Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy,” J Hepatol, vol. 73, no. 6, pp. 1526–1547, Dec. 2020, doi: 10.1016/j.jhep.2020.07.013. DOI: https://doi.org/10.1016/j.jhep.2020.07.013
[66] V. Felipo, “Hepatic encephalopathy: effects of liver failure on brain function,” Nat Rev Neurosci, vol. 14, no. 12, pp. 851–858, Dec. 2013, doi: 10.1038/nrn3587. DOI: https://doi.org/10.1038/nrn3587
[67] K. Kjærgaard et al., “Cognitive dysfunction in early experimental metabolic dysfunction-associated steatotic liver disease is associated with systemic inflammation and neuroinflammation,” JHEP Reports, vol. 6, no. 3, p. 100992, Mar. 2024, doi: 10.1016/j.jhepr.2023.100992. DOI: https://doi.org/10.1016/j.jhepr.2023.100992
[68] R. P. C. Santos, E. C. de B. Toscano, and M. A. Rachid, “Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies,” Arq Neuropsiquiatr, vol. 81, no. 07, pp. 656–669, Jul. 2023, doi: 10.1055/s-0043-1767819. DOI: https://doi.org/10.1055/s-0043-1767819
[69] M. Pasparakis and P. Vandenabeele, “Necroptosis and its role in inflammation,” Nature, vol. 517, no. 7534, pp. 311–320, Jan. 2015, doi: 10.1038/nature14191. DOI: https://doi.org/10.1038/nature14191
[70] K. Orzeł-Gajowik, K. Milewski, and M. Zielińska, “miRNA-ome plasma analysis unveils changes in blood–brain barrier integrity associated with acute liver failure in rats,” Fluids Barriers CNS, vol. 20, no. 1, p. 92, Dec. 2023, doi: 10.1186/s12987-023-00484-7. DOI: https://doi.org/10.1186/s12987-023-00484-7
[71] S. R. Archie, A. Al Shoyaib, and L. Cucullo, “Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview,” Pharmaceutics, vol. 13, no. 11, p. 1779, Oct. 2021, doi: 10.3390/pharmaceutics13111779. DOI: https://doi.org/10.3390/pharmaceutics13111779
[72] K. Song et al., “Oxidative Stress-Mediated Blood-Brain Barrier (BBB) Disruption in Neurological Diseases,” Oxid Med Cell Longev, vol. 2020, pp. 1–27, Jul. 2020, doi: 10.1155/2020/4356386. DOI: https://doi.org/10.1155/2020/4356386
[73] D. M. A. Elsherbini et al., “Astrocytes profiling in acute hepatic encephalopathy: Possible enrolling of glial fibrillary acidic protein, tumor necrosis factor-alpha, inwardly rectifying potassium channel (Kir 4.1) and aquaporin-4 in rat cerebral cortex,” Front Cell Neurosci, vol. 16, Aug. 2022, doi: 10.3389/fncel.2022.896172. DOI: https://doi.org/10.3389/fncel.2022.896172
[74] V. Jaeger, S. DeMorrow, and M. McMillin, “The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy,” J Clin Transl Hepatol, vol. 7, no. X, pp. 1–10, Dec. 2019, doi: 10.14218/JCTH.2019.00025. DOI: https://doi.org/10.14218/JCTH.2019.00025
[75] N. Zabaleta, M. Hommel, D. Salas, and G. Gonzalez-Aseguinolaza, “Genetic-Based Approaches to Inherited Metabolic Liver Diseases,” Hum Gene Ther, vol. 30, no. 10, pp. 1190–1203, Oct. 2019, doi: 10.1089/hum.2019.140. DOI: https://doi.org/10.1089/hum.2019.140
[76] J. H. Shin, J. Lee, Y. K. Jung, K. S. Kim, J. Jeong, and D. Choi, “Therapeutic applications of gene editing in chronic liver diseases: an update,” BMB Rep, vol. 55, no. 6, pp. 251–258, Jun. 2022, doi: 10.5483/BMBRep.2022.55.6.033. DOI: https://doi.org/10.5483/BMBRep.2022.55.6.033
[77] J. Baruteau, N. Brunetti‐Pierri, and P. Gissen, “Liver‐directed gene therapy for inherited metabolic diseases,” J Inherit Metab Dis, vol. 47, no. 1, pp. 9–21, Jan. 2024, doi: 10.1002/jimd.12709.
[78] L. Torella, N. Santana‐Gonzalez, N. Zabaleta, and G. Gonzalez Aseguinolaza, “Gene editing in liver diseases,” FEBS Lett, Jul. 2024, doi: 10.1002/1873-3468.14989. DOI: https://doi.org/10.1002/1873-3468.14989
[79] A. Bakrania, Y. Mo, G. Zheng, and M. Bhat, “RNA nanomedicine in liver diseases,” Hepatology, Aug. 2024, doi: 10.1097/HEP.0000000000000606. DOI: https://doi.org/10.1097/HEP.0000000000000606
[80] Q.-C. Wang, “RNA interference: Antiviral weapon and beyond,” World J Gastroenterol, vol. 9, no. 8, p. 1657, 2003, doi: 10.3748/wjg.v9.i8.1657. DOI: https://doi.org/10.3748/wjg.v9.i8.1657
[81] L. J. Scott, “Givosiran: First Approval,” Drugs, vol. 80, no. 3, pp. 335–339, Feb. 2020, doi: 10.1007/s40265-020-01269-0. DOI: https://doi.org/10.1007/s40265-020-01269-0
[82] M. M. Zhang, R. Bahal, T. P. Rasmussen, J. E. Manautou, and X. Zhong, “The growth of siRNA-based therapeutics: Updated clinical studies,” Biochem Pharmacol, vol. 189, p. 114432, Jul. 2021, doi: 10.1016/j.bcp.2021.114432. DOI: https://doi.org/10.1016/j.bcp.2021.114432
[83] A.-M. Yu and M.-J. Tu, “Deliver the promise: RNAs as a new class of molecular entities for therapy and vaccination,” Pharmacol Ther, vol. 230, p. 107967, Feb. 2022, doi: 10.1016/j.pharmthera.2021.107967. DOI: https://doi.org/10.1016/j.pharmthera.2021.107967
[84] D. Adams et al., “Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial,” Amyloid, vol. 30, no. 1, pp. 18–26, Jan. 2023, doi: 10.1080/13506129.2022.2091985. DOI: https://doi.org/10.1080/13506129.2022.2091985
[85] P. Espíritu-Ramírez et al., “Gene Therapy for Treatment of Chronic Hyperammonemia in a Rat Model of Hepatic Encephalopathy,” Ann Hepatol, vol. 17, no. 6, pp. 1026–1034, Nov. 2018, doi: 10.5604/01.3001.0012.7203. DOI: https://doi.org/10.5604/01.3001.0012.7203
[86] J. Baruteau, N. Brunetti‐Pierri, and P. Gissen, “Liver‐directed gene therapy for inherited metabolic diseases,” J Inherit Metab Dis, vol. 47, no. 1, pp. 9–21, Jan. 2024, doi: 10.1002/jimd.12709. DOI: https://doi.org/10.1002/jimd.12709
[87] R. Chu, Y. Wang, J. Kong, T. Pan, Y. Yang, and J. He, “Lipid nanoparticles as the drug carrier for targeted therapy of hepatic disorders,” J Mater Chem B, vol. 12, no. 20, pp. 4759–4784, 2024, doi: 10.1039/D3TB02766J. DOI: https://doi.org/10.1039/D3TB02766J
[88] A. Gil-Gómez, R. Muñoz-Hernández, F. Martínez, F. Jiménez, and M. Romero-Gómez, “Hepatic encephalopathy: experimental drugs in development and therapeutic potential,” Expert Opin Investig Drugs, pp. 1–12, Nov. 2024, doi: 10.1080/13543784.2024.2434053. DOI: https://doi.org/10.1080/13543784.2024.2434053
[89] G. J. Hoilat, F. K. Suhail, T. Adhami, and S. John, “Evidence-based approach to management of hepatic encephalopathy in adults,” World J Hepatol, vol. 14, no. 4, pp. 670–681, Apr. 2022, doi: 10.4254/wjh.v14.i4.670. DOI: https://doi.org/10.4254/wjh.v14.i4.670
[90] T. Sun, M. Feng, A. Manyande, H. Xiang, J. Xiong, and Z. He, “Regulation of mild cognitive impairment associated with liver disease by humoral factors derived from the gastrointestinal tract and MRI research progress: a literature review,” Front Neurosci, vol. 17, Jun. 2023, doi: 10.3389/fnins.2023.1206417. DOI: https://doi.org/10.3389/fnins.2023.1206417
[91] C. Konkwo, S. Chowdhury, and S. Vilarinho, “Genetics of liver disease in adults,” Hepatol Commun, vol. 8, no. 4, Apr. 2024, doi: 10.1097/HC9.0000000000000408. DOI: https://doi.org/10.1097/HC9.0000000000000408
[92] Y. Wang et al., “Identifying Minimal Hepatic Encephalopathy: A New Perspective from Magnetic Resonance Imaging,” Journal of Magnetic Resonance Imaging, Dec. 2023, doi: 10.1002/jmri.29179. DOI: https://doi.org/10.1002/jmri.29179
[93] P. Vidal-Cevallos, N. C. Chávez-Tapia, and M. Uribe, “Current approaches to hepatic encephalopathy,” Ann Hepatol, vol. 27, no. 6, p. 100757, Nov. 2022, doi: 10.1016/j.aohep.2022.100757. DOI: https://doi.org/10.1016/j.aohep.2022.100757
[94] A. Gil-Gómez et al., “Development and Validation of a Clinical-Genetic Risk Score to Predict Hepatic Encephalopathy in Patients With Liver Cirrhosis,” American Journal of Gastroenterology, vol. 116, no. 6, pp. 1238–1247, Jun. 2021, doi: 10.14309/ajg.0000000000001164. DOI: https://doi.org/10.14309/ajg.0000000000001164
[95] L. Boeri, L. Izzo, L. Sardelli, M. Tunesi, D. Albani, and C. Giordano, “Advanced Organ-on-a-Chip Devices to Investigate Liver Multi-Organ Communication: Focus on Gut, Microbiota and Brain,” Bioengineering, vol. 6, no. 4, p. 91, Sep. 2019, doi: 10.3390/bioengineering6040091. DOI: https://doi.org/10.3390/bioengineering6040091
[96] R. Zhu, L. Liu, G. Zhang, J. Dong, Z. Ren, and Z. Li, “The pathogenesis of gut microbiota in hepatic encephalopathy by the gut–liver–brain axis,” Biosci Rep, vol. 43, no. 6, Jun. 2023, doi: 10.1042/BSR20222524. DOI: https://doi.org/10.1042/BSR20222524
[97] H. M. Wadei, M. L. Mai, N. Ahsan, and T. A. Gonwa, “Hepatorenal Syndrome,” Clinical Journal of the American Society of Nephrology, vol. 1, no. 5, pp. 1066–1079, Sep. 2006, doi: 10.2215/CJN.01340406. DOI: https://doi.org/10.2215/CJN.01340406
[98] F. Salerno, A. Gerbes, P. Ginès, F. Wong, and V. Arroyo, “Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis,” Postgrad Med J, vol. 84, no. 998, pp. 662–670, Dec. 2008, doi: 10.1136/gut.2006.107789. DOI: https://doi.org/10.1136/gut.2006.107789
[99] A. P. Betrosian, “Acute renal dysfunction in liver diseases,” World J Gastroenterol, vol. 13, no. 42, p. 5552, 2007, doi: 10.3748/wjg.v13.i42.5552. DOI: https://doi.org/10.3748/wjg.v13.i42.5552
[100] B. Bonaz, V. Sinniger, and S. Pellissier, “The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract,” Front Immunol, vol. 8, Nov. 2017, doi: 10.3389/fimmu.2017.01452. DOI: https://doi.org/10.3389/fimmu.2017.01452
[101] T. D. Schiano, “Treatment Options for Hepatic Encephalopathy,” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, vol. 30, no. 5P2, May 2010, doi: 10.1592/phco.30.pt2.16S. DOI: https://doi.org/10.1592/phco.30.pt2.16S
[102] A.-E. Hopp et al., “P: 10 Hepatic Encephalopathy Is Reversible in the Long-term after Liver Transplantation,” American Journal of Gastroenterology, vol. 114, no. 1, pp. S4–S4, Sep. 2019, doi: 10.14309/01.ajg.0000582016.05669.1b. DOI: https://doi.org/10.14309/01.ajg.0000582016.05669.1b
[103] H. Tilg, P. D. Cani, and E. A. Mayer, “Gut microbiome and liver diseases,” Gut, vol. 65, no. 12, pp. 2035–2044, Dec. 2016, doi: 10.1136/gutjnl-2016-312729. DOI: https://doi.org/10.1136/gutjnl-2016-312729
[104] L. Ridola, “The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies,” Ann Gastroenterol, 2018, doi: 10.20524/aog.2018.0232. DOI: https://doi.org/10.20524/aog.2018.0232
[105] M. Swaminathan, M. Ellul, and T. Cross, “Hepatic encephalopathy: current challenges and future prospects,” Hepat Med, vol. Volume 10, pp. 1–11, Mar. 2018, doi: 10.2147/HMER.S118964. DOI: https://doi.org/10.2147/HMER.S118964
[106] J. M. Schattenberg, N. Chalasani, and N. Alkhouri, “Artificial Intelligence Applications in Hepatology,” Clinical Gastroenterology and Hepatology, vol. 21, no. 8, pp. 2015–2025, Jul. 2023, doi: 10.1016/j.cgh.2023.04.007. DOI: https://doi.org/10.1016/j.cgh.2023.04.007
[107] J. C. Ahn, A. Connell, D. A. Simonetto, C. Hughes, and V. H. Shah, “Application of Artificial Intelligence for the Diagnosis and Treatment of Liver Diseases,” Hepatology, vol. 73, no. 6, pp. 2546–2563, Jun. 2021, doi: 10.1002/hep.31603. DOI: https://doi.org/10.1002/hep.31603
[108] J. Louissaint and H. E. Vargas, “Picture Perfect: Artificial Intelligence in the Management of Hepatic Encephalopathy,” American Journal of Gastroenterology, vol. 119, no. 5, pp. 801–802, May 2024, doi: 10.14309/ajg.0000000000002659.
[109] N. B. Ozturk and E. B. Tapper, “The rise of mobile apps for the management of chronic liver disease,” Hepatol Commun, vol. 8, no. 4, Apr. 2024, doi: 10.1097/HC9.0000000000000429. DOI: https://doi.org/10.1097/HC9.0000000000000429
[110] K. Kazankov et al., “Evaluation of CirrhoCare® – a digital health solution for home management of individuals with cirrhosis,” J Hepatol, vol. 78, no. 1, pp. 123–132, Jan. 2023, doi: 10.1016/j.jhep.2022.08.034. DOI: https://doi.org/10.1016/j.jhep.2022.08.034
[111] B. McGuire and M. Al Sibae, “Current trends in the treatment of hepatic encephalopathy,” Ther Clin Risk Manag, p. 617, Jul. 2009, doi: 10.2147/TCRM.S4443. DOI: https://doi.org/10.2147/TCRM.S4443
[112] A. Mancini, F. Campagna, P. Amodio, and K. M. Tuohy, “Gut : liver : brain axis: the microbial challenge in the hepatic encephalopathy,” Food Funct, vol. 9, no. 3, pp. 1373–1388, 2018, doi: 10.1039/C7FO01528C. DOI: https://doi.org/10.1039/C7FO01528C
[113] J. Liu, Y. Xu, and B. Jiang, “Novel Insights Into Pathogenesis and Therapeutic Strategies of Hepatic Encephalopathy, From the Gut Microbiota Perspective,” Front Cell Infect Microbiol, vol. 11, Feb. 2021, doi: 10.3389/fcimb.2021.586427. DOI: https://doi.org/10.3389/fcimb.2021.586427
[114] J. Rozga, “Liver support technology – an update,” Xenotransplantation, vol. 13, no. 5, pp. 380–389, Sep. 2006, doi: 10.1111/j.1399-3089.2006.00323.x. DOI: https://doi.org/10.1111/j.1399-3089.2006.00323.x
[115] R. Gaspari et al., “Molecular Adsorbent Recirculating System in Liver Transplantation: Safety and Efficacy,” Transplant Proc, vol. 38, no. 10, pp. 3544–3551, Dec. 2006, doi: 10.1016/j.transproceed.2006.10.032. DOI: https://doi.org/10.1016/j.transproceed.2006.10.032
[116] J. Louissaint and H. E. Vargas, “Picture Perfect: Artificial Intelligence in the Management of Hepatic Encephalopathy,” American Journal of Gastroenterology, vol. 119, no. 5, pp. 801–802, May 2024, doi: 10.14309/ajg.0000000000002659. DOI: https://doi.org/10.14309/ajg.0000000000002659
[117] H. Wazir et al., “Diagnosis and Treatment of Liver Disease: Current Trends and Future Directions,” Cureus, Dec. 2023, doi: 10.7759/cureus.49920 DOI: https://doi.org/10.7759/cureus.49920
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