Pathomorphology of severe Grade 3-4 hepatic encephalopathy in decompensated cirrhosis patients with acute-on-chronic liver failure

T.V. Shulyatnikova; V.O. Tumanskiy; L.M.  Tumanska

doi:10.26641/2307-0404.2024.2.307482

Authors

T.V. Shulyatnikova Zaporizhzhіa State Medical and Pharmaceutical University, Maiakovskyi av., 26, Zaporizhzhia, 69035, Ukraine https://orcid.org/0000-0002-0196-9935
V.O. Tumanskiy Zaporizhzhіa State Medical and Pharmaceutical University, Maiakovskyi av., 26, Zaporizhzhia, 69035, Ukraine https://orcid.org/0000-0001-8267-2350
L.M. Tumanska Zaporizhzhіa State Medical and Pharmaceutical University, Maiakovskyi av., 26, Zaporizhzhia, 69035, Ukraine https://orcid.org/0000-0001-5715-0040

DOI:

https://doi.org/10.26641/2307-0404.2024.2.307482

Keywords:

hepatic encephalopathy, liver cirrhosis, neuropathology, immunohistochemistry, ammonia, Alzheimer type 2 astrocytes, ameboid microglia, amyloid bodies

Abstract

The study was aimed to determine of the most significant pathomorphological signs of severe hepatic encephalopathy (HE) in deceased cirrhotic patients with acute-on-chronic liver failure (ACLF) syndrome based on changes of the glioneuronal complex and the level of tissue ammonia. Using pathohistological, histochemical, and immunohistochemical methods, the cerebral cortex, thalamus, striatum, and cerebellum of 21 deceased patients with acutely decompensated liver cirrhosis with ACLF syndrome and HE Grade 3-4 were examined in comparison with control group, which included 30 deceased patients from acute cardiovascular failure. The study revealed that during HE Grade 3-4 as a component of ACLF, in all studied brain regions, there was a reliably (p<0.05) higher histochemical level of tissue ammonia (up to 500%), increased numbers (up to 215.69%) of apoptotic neurons (according to caspase-3), reduced (up to 119.60%) level of synaptophysin, increased expression of glutamine synthetase (up to 253.02%) and aquaporin-4 (up to 481.81%) associated by reduced (up to 296.81%) expression of glial fibrillary acidic protein in astrocytes, increased (up to 11-fold) numbers of Alzheimer type 2-astrocytes, expansion of perivascular and pericellular «edematous» spaces (up to 890.81%), increased numbers of amyloid bodies (up to 5-fold), increased area of immunopositive material of CD68+ microgliocytes (up to 114.78%) with an increase (up to 71.91%) in the proportion of CD68+ amoeboid microglia. The above-mentioned changes confirm that the loss of consciousness and other psychoneurological manifestations of severe HE Grade 3-4 are due to compound ammonia-associated changes in the components of the glioneuronal complex, namely: adaptive remodeling and dystrophic changes in astrocytes, reduced synaptic transmission and apoptotic neuronal death, reactive changes in microglia with a small proportion of microgliocytes involved in phagocytosis, cytotoxic brain edema and dysfunction of the glymphatic system

References

Butterworth RF. Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology. Drugs. 2019 Feb;79(Suppl 1):17-21. doi: https://doi.org/10.1007/s40265-018-1017-0

Görg B, Karababa A, Häussinger D. Hepatic Encephalopathy and Astrocyte Senescence. J Clin Exp Hepatol. 2018 Sep;8(3):294-300. doi: https://doi.org/10.1016/j.jceh.2018.05.003

Elsherbini DMA, Ghoneim FM, El-Mancy EM, Ebrahim HA, El-Sherbiny M, El-Shafey M, et al. Astro-cytes 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. 2022 Aug 17;16:896172. doi: https://doi.org/10.3389/fncel.2022.896172

Shulyatnikova TV, Tumanskiy VO. Ammonia level and Alzheimer type 2 astrocytes in the brain of deceased patients with liver cirrhosis of the varying degree. Pathologia. 2023 Apr 280;20(1):36-44. doi: https://doi.org/10.14739/2310-1237.2023.1.276453

Arroyo V, Moreau R, Jalan R. Acute-on-Chronic Liver Failure. N Engl J Med. 2020 May 28;382(22):2137-45. doi: https://doi.org/10.1056/NEJMra1914900

Engelmann C, Berg T. Clinical practice guidelines for acute-on-chronic liver failure: are we ready for reaching global consensus? Hepatobiliary Surg Nutr. 2023 Apr 10;12(2):239-43. doi: https://doi.org/10.21037/hbsn-23-6

Zaccherini G, Weiss E, Moreau R. Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment. JHEP Rep. 2020 Sep 2;3(1):100176. doi: https://doi.org/10.1016/j.jhepr.2020.100176

Nakadate K, Sono C, Mita H, Itakura Y, Kawakami K. Severe Acute Liver Dysfunction Induces Delayed Hepatocyte Swelling and Cytoplasmic Vacuolization, and Delayed Cortical Neuronal Cell Death. Int J Mol Sci. 2023 Apr 16;24(8):7351. doi: https://doi.org/10.3390/ijms24087351

Kok B, Abraldes JG. Child-Pugh Classification: Time to Abandon? Semin Liver Dis. 2019 Feb;39(1):96-103. doi: https://doi.org/10.1055/s-0038-1676805

10.Gutiérrez-de-Juan V, López de Davalillo S, Fernández-Ramos D, Barbier-Torres L, Zubiete-Franco I, Fernández-Tussy P, Simon J, Lopitz-Otsoa F, de las Heras J, Iruzubieta P, Avila MA. A morphological method for ammonia detection in liver. PLOS ONE [Internet]. 2017Mar.20;12(3):e0173914. Available from: https://dx.plos.org/10.1371/journal.pone.0173914

Antomonov MYu. [Mathematical processing and analysis of medical and biological data. 2nd ed.]. Кyiv: "Medinform"; 2018. 579 р. Russian.

Lu K. Cellular Pathogenesis of Hepatic Encepha-lopathy: An Update. Biomolecules. 2023 Feb 19;13(2):396. doi: https://doi.org/10.3390/biom13020396

Jayakumar AR, Norenberg MD. Hyperammone-mia in Hepatic Encephalopathy. J Clin Exp Hepat. 2018;8(3):272-80. doi: https://doi.org/10.1016/j.jceh.2018.06.007

Angelova PR, Kerbert AJC, Habtesion A, Hall A, Abramov AY, Jalan R. Hyperammonaemia induces mitochondrial dysfunction and neuronal cell death. JHEP Rep. 2022 May 23;4(8):100510. doi: https://doi.org/10.1016/j.jhepr.2022.100510

Popek M, Bobula B, Sowa J, Hess G, Polowy R, Filipkowski RK, et al. Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events. Mol Neurobiol. 2018 Feb;55(2):1244-58. doi: https://doi.org/10.1007/s12035-016-0367-4

Häussinger D, Dhiman RK, Felipo V, Görg B, Jalan R, Kircheis G, et al. Hepatic encephalopathy. Nat Rev Dis Primers. 2022 Jun 23;8(1):43. doi: https://doi.org/10.1038/s41572-022-00366-6

Jaeger V, DeMorrow S, McMillin M. The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy. J Clin Transl Hepatol. 2019 Dec 28;7(4):352-61. doi: https://doi.org/10.14218/JCTH.2019.00025

Claeys W, Van Hoecke L, Lefere S, Geerts A, Verhelst X, Van Vlierberghe H, et al. The neurogliovascular unit in hepatic encephalopathy. JHEP Rep. 2021 Aug 11;3(5):100352. doi: https://doi.org/10.1016/j.jhepr.2021.100352

19.Augé E, Bechmann I, Llor N, Vilaplana J, Krueger M, Pelegrí C. Corpora amylacea in human hippocampal brain tissue are intracellular bodies that exhibit a homogeneous distribution of neo-epitopes. Scientific Reports [Internet]. 2019Feb.14;9(1). Available from: https://www.nature.com/articles/s41598-018-38010-7

Riba M, Augé E, Campo-Sabariz J, Moral-Anter D, Molina-Porcel L, Ximelis T, et al. Corpora amylacea act as containers that remove waste products from the brain. Proc Natl Acad Sci USA. 2019 Dec 17;116(51):26038-48. doi: https://doi.org/10.1073/pnas.1913741116

Agarwal AN, Mais DD. Sensitivity and Specificity of Alzheimer Type II Astrocytes in Hepatic Encepha-lopathy. Arch Pathol Lab Med. 2019 Oct;143(10):1256-8. doi: https://doi.org/10.5858/arpa.2018-0455-OA

Zemtsova I, Görg B, Keitel V, Bidmon HJ, Schrör K, Häussinger D. Microglia activation in hepatic encephalopathy in rats and humans. Hepatology. 2011 Jul;54(1):204-15. doi: https://doi.org/10.1002/hep.24326