Exploration of Digestive Diseases

Factor	Mechanism
Hyperammonemia	Impaired liver detoxification→ammonia crosses blood-brain barrier→neuronal dysfunction
Systemic inflammation	Gut dysbiosis→endotoxemia→elevated TNF-α/IL-6→neuroinflammation
Gut-brain axis	Dysbiosis→increased ammonia/endotoxins→systemic and brain inflammation

Declarations

Acknowledgments

The author would like to thank her respective institution for providing access to the scholarly resources used in this narrative review.

Author contributions

MG: Conceptualization, Writing—original draft, Writing—review & editing. The author has read and approved the final version of the manuscript.

Conflicts of interest

The author declares that there are no conflicts of interest.

Ethical approval

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References

Faccioli J, Nardelli S, Gioia S, Riggio O, Ridola L. Minimal Hepatic Encephalopathy Affects Daily Life of Cirrhotic Patients: A Viewpoint on Clinical Consequences and Therapeutic Opportunities. J Clin Med. 2022;11:7246. [DOI] [PubMed] [PMC]

Moran S, López-Sánchez M, Milke-García MDP, Rodríguez-Leal G. Current approach to treatment of minimal hepatic encephalopathy in patients with liver cirrhosis. World J Gastroenterol. 2021;27:3050–63. [DOI] [PubMed] [PMC]

Nardone R, Taylor AC, Höller Y, Brigo F, Lochner P, Trinka E. Minimal hepatic encephalopathy: A review. Neurosci Res. 2016;111:1–12. [DOI] [PubMed]

Ridola L, Nardelli S, Gioia S, Riggio O. Quality of life in patients with minimal hepatic encephalopathy. World J Gastroenterol. 2018;24:5446–53. [DOI] [PubMed] [PMC]

Lv XH, Lu Q, Deng K, Yang JL, Yang L. Prevalence and Characteristics of Covert/Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Systematic Review and Meta-Analysis. Am J Gastroenterol. 2024;119:690–9. [DOI] [PubMed]

Gairing SJ, Mangini C, Zarantonello L, Gioia S, Nielsen EJ, Danneberg S, et al. Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Multicenter Study. Am J Gastroenterol. 2023;118:2191–200. [DOI] [PubMed]

American Association for the Study of Liver Diseases; European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014;61:642–59. [DOI] [PubMed]

Zhu R, Liu L, Zhang G, Dong J, Ren Z, Li Z. The pathogenesis of gut microbiota in hepatic encephalopathy by the gut-liver-brain axis. Biosci Rep. 2023;43:BSR20222524. [DOI] [PubMed] [PMC]

Butterworth RF. Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology. Drugs. 2019;79:17–21. [DOI] [PubMed] [PMC]

10.

Cabrera-Pastor A, Llansola M, Montoliu C, Malaguarnera M, Balzano T, Taoro-Gonzalez L, et al. Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications. Acta Physiol (Oxf). 2019;226:e13270. [DOI] [PubMed]

11.

Ntuli Y, Shawcross DL. Infection, inflammation and hepatic encephalopathy from a clinical perspective. Metab Brain Dis. 2024;39:1689–703. [DOI] [PubMed] [PMC]

12.

Mangas-Losada A, García-García R, Urios A, Escudero-García D, Tosca J, Giner-Durán R, et al. Minimal hepatic encephalopathy is associated with expansion and activation of CD⁴⁺CD28^-, Th22 and Tfh and B lymphocytes. Sci Rep. 2017;7:6683. [DOI] [PubMed] [PMC]

13.

Kang DJ, Betrapally NS, Ghosh SA, Sartor RB, Hylemon PB, Gillevet PM, et al. Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice. Hepatology. 2016;64:1232–48. [DOI] [PubMed] [PMC]

14.

Ahluwalia V, Betrapally NS, Hylemon PB, White MB, Gillevet PM, Unser AB, et al. Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis. Sci Rep. 2016;6:26800. [DOI] [PubMed] [PMC]

15.

Prakash RK, Kanna S, Mullen KD. Evolving concepts: the negative effect of minimal hepatic encephalopathy and role for prophylaxis in patients with cirrhosis. Clin Ther. 2013;35:1458–73. [DOI] [PubMed]

16.

Nardelli S, Gioia S, Faccioli J, Riggio O, Ridola L. Sarcopenia and cognitive impairment in liver cirrhosis: A viewpoint on the clinical impact of minimal hepatic encephalopathy. World J Gastroenterol. 2019;25:5257–65. [DOI] [PubMed] [PMC]

17.

Kappus MR, Bajaj JS. Covert hepatic encephalopathy: not as minimal as you might think. Clin Gastroenterol Hepatol. 2012;10:1208–19. [DOI] [PubMed]

18.

Bajaj JS. Minimal hepatic encephalopathy matters in daily life. World J Gastroenterol. 2008;14:3609–15. [DOI] [PubMed] [PMC]

19.

Giménez-Garzó C, Garcés JJ, Urios A, Mangas-Losada A, García-García R, González-López O, et al. The PHES battery does not detect all cirrhotic patients with early neurological deficits, which are different in different patients. PLoS One. 2017;12:e0171211. [DOI] [PubMed] [PMC]

20.

Zeng X, Zhang L, Liu Q, Lu C, Wei J, Shi Z, et al. Combined Scores from the EncephalApp Stroop Test, Number Connection Test B, and Serial Dotting Test Accurately Identify Patients With Covert Hepatic Encephalopathy. Clin Gastroenterol Hepatol. 2020;18:1618–25.e7. [DOI] [PubMed]

21.

Hansen MKG, Kjærgaard K, Eriksen LL, Grønkjær LL, Mikkelsen ACD, Sandahl TD, et al. Psychometric methods for diagnosing and monitoring minimal hepatic encephalopathy —current validation level and practical use. Metab Brain Dis. 2022;37:589–605. [DOI] [PubMed]

22.

Allampati S, Duarte-Rojo A, Thacker LR, Patidar KR, White MB, Klair JS, et al. Diagnosis of Minimal Hepatic Encephalopathy Using Stroop EncephalApp: A Multicenter US-Based, Norm-Based Study. Am J Gastroenterol. 2016;111:78–86. [DOI] [PubMed]

23.

Luo M, Hu FR, Wang PD, Yao L, Hu SJ, Bai FH. EncephalApp stroop test versus electronic number connection test-A for screening minimal hepatic encephalopathy in patients with liver cirrhosis: a comparative study. Scand J Gastroenterol. 2022;57:1066–9. [DOI] [PubMed]

24.

Acharya C, Shaw J, Duong N, Fagan A, McGeorge S, Wade JB, et al. QuickStroop, a Shortened Version of EncephalApp, Detects Covert Hepatic Encephalopathy With Similar Accuracy Within One Minute. Clin Gastroenterol Hepatol. 2023;21:136–42. [DOI] [PubMed] [PMC]

25.

Singhal A, Nagarajan R, Kumar R, Huda A, Gupta RK, Thomas MA. Magnetic resonance T₂-relaxometry and 2D L-correlated spectroscopy in patients with minimal hepatic encephalopathy. J Magn Reson Imaging. 2009;30:1034–41. [DOI] [PubMed] [PMC]

26.

Amodio P, Campagna F, Olianas S, Iannizzi P, Mapelli D, Penzo M, et al. Detection of minimal hepatic encephalopathy: normalization and optimization of the Psychometric Hepatic Encephalopathy Score. A neuropsychological and quantified EEG study. J Hepatol. 2008;49:346–53. [DOI] [PubMed]

27.

Yadav SK, Goel A, Saraswat VA, Thomas MA, Wang E, Marincola FM, et al. Evaluation of cognitivity, proinflammatory cytokines, and brain magnetic resonance imaging in minimal hepatic encephalopathy induced by cirrhosis and extrahepatic portal vein obstruction. J Gastroenterol Hepatol. 2016;31:1986–94. [DOI] [PubMed]

28.

Li JL, Jiang H, Zhang XD, Huang LX, Xie SS, Zhang L, et al. Microstructural brain abnormalities correlate with neurocognitive dysfunction in minimal hepatic encephalopathy: a diffusion kurtosis imaging study. Neuroradiology. 2019;61:685–94. [DOI] [PubMed]

29.

Chen HJ, Chen R, Yang M, Teng GJ, Herskovits EH. Identification of minimal hepatic encephalopathy in patients with cirrhosis based on white matter imaging and Bayesian data mining. AJNR Am J Neuroradiol. 2015;36:481–7. [DOI] [PubMed] [PMC]

30.

Razek AAKA, Abdalla A, Ezzat A, Megahed A, Barakat T. Minimal hepatic encephalopathy in children with liver cirrhosis: diffusion-weighted MR imaging and proton MR spectroscopy of the brain. Neuroradiology. 2014;56:885–91. [DOI] [PubMed]

31.

Chen LH, Shi JY, Zou TX, Zhang L, Gou Y, Lin Y, et al. Disturbance of thalamic metabolism and its association with regional neural dysfunction and cognitive impairment in minimal hepatic encephalopathy. Eur J Radiol. 2020;131:109252. [DOI] [PubMed]

32.

Zeng G, Penninkilampi R, Chaganti J, Montagnese S, Brew BJ, Danta M. Meta-analysis of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy. Neurology. 2020;94:e1147–56. [DOI] [PubMed]

33.

Montoliu C, Cauli O, Urios A, ElMlili N, Serra MA, Giner-Duran R, et al. 3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis. Am J Gastroenterol. 2011;106:1629–37. [DOI] [PubMed]

34.

Rubio T, Felipo V, Tarazona S, Pastorelli R, Escudero-García D, Tosca J, et al. Multi-omic analysis unveils biological pathways in peripheral immune system associated to minimal hepatic encephalopathy appearance in cirrhotic patients. Sci Rep. 2021;11:1907. [DOI] [PubMed] [PMC]

35.

Jiménez B, Montoliu C, MacIntyre DA, Serra MA, Wassel A, Jover M, et al. Serum metabolic signature of minimal hepatic encephalopathy by ¹H-nuclear magnetic resonance. J Proteome Res. 2010;9:5180–7. [DOI] [PubMed]

36.

Dhiman RK, Thumburu KK, Verma N, Chopra M, Rathi S, Dutta U, et al. Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis. Clin Gastroenterol Hepatol. 2020;18:800–12.e25. [DOI] [PubMed]

37.

Wang MW, Ma WJ, Wang Y, Ma XH, Xue YF, Guan J, et al. Comparison of the effects of probiotics, rifaximin, and lactulose in the treatment of minimal hepatic encephalopathy and gut microbiota. Front Microbiol. 2023;14:1091167. [DOI] [PubMed] [PMC]

38.

Luo M, Xin RJ, Hu FR, Yao L, Hu SJ, Bai FH. Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis. World J Gastroenterol. 2023;29:144–56. [DOI] [PubMed] [PMC]

39.

Bloom PP, Tapper EB, Young VB, Lok AS. Microbiome therapeutics for hepatic encephalopathy. J Hepatol. 2021;75:1452–64. [DOI] [PubMed] [PMC]

40.

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;39:1441–9. [DOI] [PubMed]

41.

Gairing SJ, Mangini C, Zarantonello L, Gioia S, Nielsen EJ, Danneberg S, et al. Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival. J Intern Med. 2024;295:331–45. [DOI] [PubMed]

42.

Nardelli S, Gioia S, Ridola L, Farcomeni A, Merli M, Riggio O. Proton Pump Inhibitors Are Associated With Minimal and Overt Hepatic Encephalopathy and Increased Mortality in Patients With Cirrhosis. Hepatology. 2019;70:640–9. [DOI] [PubMed]