Key astroglial markers in human liver cirrhosis of different degree: immunohistochemical study
Keywords:liver cirrhosis, astroglia, reactivity, GFAP, GS, AQP4, hepatic encephalopathy, immunohistochemistry
The aim of the study – determining the immunohistochemical levels of the GFAP, GS and AQP4 in different regions of the human brain in the conditions of liver cirrhosis of different degree.
Materials and methods. The study was performed on sectional material of 90 patients who suffered during lifetime from liver non-alcoholic cirrhosis of classes A (n = 30, group “A”), B (n = 30, group “B”) and C (n = 30, group “C”) according to Child–Pugh classification, including 59 (65.55 %) cases with clinical symptoms of I–IV grade hepatic encephalopathy. Cortex, white matter, hippocampus, thalamus, striopallidum, cerebellum, were examined using immunohistochemical method for evaluation of GFAP, GS and AQP4 levels.
Results. GFAP expression gradually decreased from classes A to C of cirrhosis. The most expressed GFAP decline was found in class C in the cortex and thalamus (6.74- and 6.23-fold decrease). Contrary to GFAP, GS expression gradually increased along with aggravation of cirrhosis. The most prominent augmentation of GS was related in the cortex and thalamus in “C” group, respectively 4.34- and 4.26-fold increase. AQP4 levels also showed growing mode correlated with cirrhosis aggravation. The highest increase was found in the cortex and thalamus in “C” group (4.25- and 4.34-fold increase, respectively). Starting from class B, altered GFAP, GS, and AQP4 levels showed region-dependent relationships. GS and AQP4 were positively correlated in all 6 studied regions, while the inverse relationships were found between GFAP vs. GS and GFAP vs. AQP4 proteins.
Conclusions. As early as in class A of cirrhosis, dynamic molecular alterations are occurred in the brain astrocytes, indicating the progressive development of astroglial remodeling with a violation of its cytoskeleton and redistribution of molecular domains within cells. This phenomenon is region- and time-specific; its signs get stronger with time from class to class, becoming most pronounced in class C. Among studied brain regions, cortex and thalamus are characterized by the most pronounced protein changes. Starting from class B, the remarkable relationship is seen between molecular changes of both direct and inverse type. Simultaneously emerging links might indicate synergistic involvement of these molecules in astroglial remodeling in chronic hepatic encephalopathy. Alterations in the mentioned astroglial molecular complex can serve both as a diagnostic marker of reactive astrogliosis during liver cirrhosis and represent a target for novel therapeutic approaches regarding encephalopathy in cirrhotic patients.
Cheemerla, S., & Balakrishnan, M. (2021). Global Epidemiology of Chronic Liver Disease. Clinical liver disease, 17(5), 365-370. https://doi.org/10.1002/cld.1061
Hirode, G., Vittinghoff, E., & Wong, R. J. (2019). Increasing Burden of Hepatic Encephalopathy Among Hospitalized Adults: An Analysis of the 2010-2014 National Inpatient Sample. Digestive diseases and sciences, 64(6), 1448-1457. https://doi.org/10.1007/s10620-019-05576-9
Pérez-Monter, C., & Torre-Delgadillo, A. (2017). Astrocyte Pathophysiology in Liver Disease. In M. T. Gentile, & L. C. D’Amato (Eds.), Astrocyte - Physiology and Pathology. IntechOpen. https://doi.org/10.5772/intechopen.72506
Amodio, P., & Montagnese, S. (2021). Lights and Shadows in Hepatic Encephalopathy Diagnosis. Journal of clinical medicine, 10(2), 341. https://doi.org/10.3390/jcm10020341
Shulyatnikova, T. V., & Shavrin, V. A. (2017). Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis. Pathologia, 14(3), 371-380. https://doi.org/10.14739/2310-1237.2017.3.118773
Weissenborn, K. (2019). Hepatic Encephalopathy: Definition, Clinical Grading and Diagnostic Principles. Drugs, 79(Suppl 1), 5-9. https://doi.org/10.1007/s40265-018-1018-z
Jaeger, V., DeMorrow, S., & McMillin, M. (2019). The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy. Journal of clinical and translational hepatology, 7(4), 352-361. https://doi.org/10.14218/JCTH.2019.00025
Liotta, E. M., & Kimberly, W. T. (2020). Cerebral edema and liver disease: Classic perspectives and contemporary hypotheses on mechanism. Neuroscience letters, 721, 134818. https://doi.org/10.1016/j.neulet.2020.134818
Jayakumar, A. R., & Norenberg, M. D. (2018). Hyperammonemia in Hepatic Encephalopathy. Journal of clinical and experimental hepatology, 8(3), 272-280. https://doi.org/10.1016/j.jceh.2018.06.007
Görg, B., Karababa, A., Schütz, E., Paluschinski, M., Schrimpf, A., Shafigullina, A., Castoldi, M., Bidmon, H. J., & Häussinger, D. (2019). O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy. Journal of hepatology, 71(5), 930-941. https://doi.org/10.1016/j.jhep.2019.06.020
Häussinger, D., Dhiman, R. K., Felipo, V., Görg, B., Jalan, R., Kircheis, G., Merli, M., Montagnese, S., Romero-Gomez, M., Schnitzler, A., Taylor-Robinson, S. D., & Vilstrup, H. (2022). Hepatic encephalopathy. Nature reviews. Disease primers, 8(1), 43. https://doi.org/10.1038/s41572-022-00366-6
Agarwal, A. N., & Mais, D. D. (2019). Sensitivity and Specificity of Alzheimer Type II Astrocytes in Hepatic Encephalopathy. Archives of pathology & laboratory medicine, 143(10), 1256-1258. https://doi.org/10.5858/arpa.2018-0455-OA
Häussinger, D., Butz, M., Schnitzler, A. & Görg, B. (2021). Pathomechanisms in hepatic encephalopathy. Biological Chemistry, 402(9), 1087-1102. https://doi.org/10.1515/hsz-2021-0168
Shulyatnikova, T. V., & Tumanskiy, V. O. (2021). Immunohistochemical analysis of the glial fibrillary acidic protein expression in the experimental acute hepatic encephalopathy. Morphologia, 15(4), 96-105.
Escartin, C., Galea, E., Lakatos, A., O'Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., Allen, N. J., Araque, A., Barbeito, L., Barzilai, A., Bergles, D. E., Bonvento, G., Butt, A. M., Chen, W. T., Cohen-Salmon, M., Cunningham, C., … Verkhratsky, A. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nature neuroscience, 24(3), 312-325. https://doi.org/10.1038/s41593-020-00783-4
Verkhratsky, A., Ho, M. S., Vardjan, N., Zorec, R., & Parpura, V. (2019). General Pathophysiology of Astroglia. Advances in experimental medicine and biology, 1175, 149-179. https://doi.org/10.1007/978-981-13-9913-8_7
Claeys, W., Van Hoecke, L., Lefere, S., Geerts, A., Verhelst, X., Van Vlierberghe, H., Degroote, H., Devisscher, L., Vandenbroucke, R. E., & Van Steenkiste, C. (2021). The neurogliovascular unit in hepatic encephalopathy. JHEP reports: innovation in hepatology, 3(5), 100352. https://doi.org/10.1016/j.jhepr.2021.100352
Zhou, Y., Eid, T., Hassel, B., & Danbolt, N. C. (2020). Novel aspects of glutamine synthetase in ammonia homeostasis. Neurochemistry international, 140, 104809. https://doi.org/10.1016/j.neuint.2020.104809
Shulyatnikova T. V., & Tumanskiy, V. O. (2021). Glutamine synthetase expression in the brain during experimental acute liver failure (immunohistochemical study). Journal of Education, Health and Sport, 11(10), 342-356. http://dx.doi.org/10.12775/JEHS.2021.11.10.033
Shulyatnikova, T. V., & Tumanskiy, V. O. (2022). Immunohistochemical study of the brain aquaporin-4 in the rat acute liver failure model. Art of Medicine, (1), 103-108. https://doi.org/10.21802/artm.2022.1.21.103
Wan, S. Z., Nie, Y., Zhang, Y., Liu, C., & Zhu, X. (2020). Assessing the Prognostic Performance of the Child-Pugh, Model for End-Stage Liver Disease, and Albumin-Bilirubin Scores in Patients with Decompensated Cirrhosis: A Large Asian Cohort from Gastroenterology Department. Disease markers, 2020, 5193028. https://doi.org/10.1155/2020/5193028
Mehta, R., GP trainee, Chinthapalli, K., & consultant neurologist (2019). Glasgow coma scale explained. BMJ (Clinical research ed.), 365, l1296. https://doi.org/10.1136/bmj.l1296
Zhou, Y., Dhaher, R., Parent, M., Hu, Q. X., Hassel, B., Yee, S. P., Hyder, F., Gruenbaum, S. E., Eid, T., & Danbolt, N. C. (2019). Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration. Neurochemistry international, 123, 22-33. https://doi.org/10.1016/j.neuint.2018.07.009
How to Cite
LicenseAuthors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access)