Altered Level of Consciousness in Metabolic Disease: An Emphasis on the Pathomechanism of Hepatic Encephalopathy
DOI:
https://doi.org/10.51601/ijhp.v6i2.548Abstract
Altered level of consciousness (ALOC) is a common clinical presentation in emergency and inpatient settings, with metabolic diseases representing as major etiologic causes. Among these, hepatic encephalopathy (HE) is one of the most frequent causes due to its high prevalence, morbidity, and mortality. HE has a complex pathophysiology mechanism involving neurotoxic substances such as ammonia. This narrative literature review discusses ALOC associated with metabolic disease, with emphasis on the underlying pathophysiological mechanisms of HE. Metabolic encephalopathy arises from systemic disturbances rather than primary structural brain injury and may progress to irreversible neuronal damage if untreated. HE develops in the context of acute liver failure, portosystemic shunting, or cirrhosis. Its pathogenesis reflects a multifactorial interaction involving hyperammonemia, systemic inflammation, gut microbiome dysbiosis, electrolyte disorders, malnutrition, sarcopenia, and manganese accumulation. Ammonia remains a central neurotoxin in HE, contributing to astrocytic swelling, glutamine accumulation, and cytotoxic edema. Inflammatory response further neuronal impairment through cytokine-mediated oxidative stress and blood–brain barrier disruption. Gut dysbiosis promotes bacterial translocation and endotoxemia, exacerbating systemic inflammation and worsening neurocognitive impairment. Given the broad differential diagnosis of ALOC, a structured clinical approach and early identification of metabolic causes especially HE is essential. Understanding the complex
Downloads
References
[1] H. A. Ali and M. F. Y. Mohamud, “Epidemiology, Risk Factors and Etiology of Altered Level of Consciousness Among Patients Attending the Emergency Department at a Tertiary Hospital in Mogadishu, Somalia,” Int. J. Gen. Med., vol. 15, pp. 5297–5306, May 2022, doi: 10.2147/IJGM.S364202.
[2] L. Patti and M. Gupta, “Change in Mental Status,” in StatPearls, Treasure Island (FL): StatPearls Publishing, 2025. Accessed: Nov. 22, 2025. [Online]. Available: http://www.ncbi.nlm.nih.gov/books/NBK441973/
[3] S. Jung, J. C. Jeon, C.-G. Jung, Y. W. Cho, and K. T. Kim, “The etiologies of altered level of consciousness in the emergency department,” J. Neurocritical Care, vol. 13, no. 2, pp. 86–91, Sep. 2020, doi: 10.18700/jnc.200010.
[4] T. Cooksley, S. Rose, and M. Holland, “A systematic approach to the unconscious patient,” Clin. Med., vol. 18, no. 1, pp. 88–92, Feb. 2018, doi: 10.7861/clinmedicine.18-1-88.
[5] I. I. Berisavac et al., “How to recognize and treat metabolic encephalopathy in Neurology intensive care unit,” Neurol. India, vol. 65, no. 1, p. 123, Feb. 2017, doi: 10.4103/0028-3886.198192.
[6] M. Tomkins, R. McCormack, K. O’Connell, A. Agha, and Á. Merwick, “Metabolic encephalopathy secondary to diabetic ketoacidosis: a case report,” BMC Endocr. Disord., vol. 19, p. 71, Jul. 2019, doi: 10.1186/s12902-019-0398-8.
[7] M. D. Sharifi, G. Latifian Esafahani, M. Foroughian, and E. Vafadar Moradi, “The Etiology of Non-traumatic Loss of Consciousness in Patients Admitted to the Emergency Department,” Arch. Neurosci., vol. 11, no. 4, Aug. 2024, doi: 10.5812/ans-146116.
[8] A. Potnis, S. VanMeter, and J. Stange, “Prevalence of Hepatic Encephalopathy from a Commercial Medical Claims Database in the United States,” Int. J. Hepatol., vol. 2021, no. 1, p. 8542179, 2021, doi: 10.1155/2021/8542179.
[9] P. Mandiga, S. Kommu, and P. C. Bollu, “Hepatic Encephalopathy,” in StatPearls, Treasure Island (FL): StatPearls Publishing, 2025. Accessed: Nov. 23, 2025. [Online]. Available: http://www.ncbi.nlm.nih.gov/books/NBK430869/
[10] 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.
[11] Z. A. Bauer, O. De Jesus, and J. L. Bunin, “Unconscious Patient,” in StatPearls, Treasure Island (FL): StatPearls Publishing, 2025. Accessed: Nov. 25, 2025. [Online]. Available: http://www.ncbi.nlm.nih.gov/books/NBK538529/
[12] M. Braun, W. U. Schmidt, M. Möckel, M. Römer, C. J. Ploner, and T. Lindner, “Coma of unknown origin in the emergency department: implementation of an in-house management routine,” Scand. J. Trauma Resusc. Emerg. Med., vol. 24, p. 61, Apr. 2016, doi: 10.1186/s13049-016-0250-3.
[13] T. Cooksley and M. Holland, “The management of coma,” Medicine (Baltimore), vol. 45, no. 2, pp. 115–119, Feb. 2017, doi: 10.1016/j.mpmed.2016.12.001.
[14] L. Mohney and R. H. Lindberg, “Metabolic Encephalopathies | PM&R KnowledgeNow.” Accessed: Nov. 28, 2025. [Online]. Available: https://now.aapmr.org/metabolic-encephalopathies/
[15] E. F. M. Wijdicks, “Identifying encephalopathies from acute metabolic derangements,” J. Intern. Med., vol. 292, no. 6, pp. 846–857, 2022, doi: 10.1111/joim.13538.
[16] J. A. Frontera et al., “Toxic Metabolic Encephalopathy in Hospitalized Patients with COVID-19,” Neurocrit. Care, vol. 35, no. 3, pp. 693–706, 2021, doi: 10.1007/s12028-021-01220-5.
[17] L. Le Guennec, C. Marois, S. Demeret, E. F. M. Wijdicks, and N. Weiss, “Toxic-metabolic encephalopathy in adults: Critical discussion and pragmatical diagnostic approach,” Rev. Neurol. (Paris), vol. 178, no. 1–2, pp. 93–104, Jan. 2022, doi: 10.1016/j.neurol.2021.11.007.
[18] S. J. Jeon, S. S. Choi, H. Y. Kim, and I. K. Yu, “Acute Acquired Metabolic Encephalopathy Based on Diffusion MRI,” Korean J. Radiol., vol. 22, no. 12, pp. 2034–2051, Dec. 2021, doi: 10.3348/kjr.2019.0303.
[19] R. Sonneville et al., “The spectrum of sepsis-associated encephalopathy: a clinical perspective,” Crit. Care, vol. 27, no. 1, p. 386, Oct. 2023, doi: 10.1186/s13054-023-04655-8.
[20] E. F. M. Wijdicks, “Hepatic Encephalopathy,” N. Engl. J. Med., vol. 375, no. 17, pp. 1660–1670, Oct. 2016, doi: 10.1056/NEJMra1600561.
[21] T. h. Tranah, A. Paolino, and D. L. Shawcross, “Pathophysiological mechanisms of hepatic encephalopathy,” Clin. Liver Dis., vol. 5, no. 3, pp. 59–63, 2015, doi: 10.1002/cld.445.
[22] 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.
[23] J. A. González-Regueiro, M. F. H. la Tijera, R. Moreno-Alcántar, and A. Torre, “Pathophysiology of hepatic encephalopathy and future treatment options,” Rev. Gastroenterol. México, vol. 84, no. 2, pp. 195–203, Apr. 2019, doi: 10.1016/j.rgmxen.2019.05.001.
[24] K. Lu, “Cellular Pathogenesis of Hepatic Encephalopathy: An Update,” Biomolecules, vol. 13, no. 2, p. 396, Feb. 2023, doi: 10.3390/biom13020396.
[25] Y. Ntuli and D. L. Shawcross, “Infection, inflammation and hepatic encephalopathy from a clinical perspective,” Metab. Brain Dis., vol. 39, no. 8, pp. 1689–1703, Dec. 2024, doi: 10.1007/s11011-024-01402-y.
[26] R. P. C. Santos, E. C. D. 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.
[27] 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.
[28] 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, p. 748253, Nov. 2021, doi: 10.3389/fcell.2021.748253.
[29] A. K. Singal et al., “ACG Clinical Guideline: Malnutrition and Nutritional Recommendations in Liver Disease,” Off. J. Am. Coll. Gastroenterol. ACG, vol. 120, no. 5, p. 950, May 2025, doi: 10.14309/ajg.0000000000003379.
[30] D. Bellafante, S. Gioia, J. Faccioli, O. Riggio, L. Ridola, and S. Nardelli, “Old and New Precipitants in Hepatic Encephalopathy: A New Look at a Field in Continuous Evolution,” J. Clin. Med., vol. 12, no. 3, p. 1187, Feb. 2023, doi: 10.3390/jcm12031187.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Steven Jonathan, I Ketut Suryana, I Made Suma Wirawan
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
