HEPATOCYTE APOPTOSIS IN THE DEVELOPMENT OF ACUTE ON CHRONIC LIVER FAILURE IN DECOMPENSATED ALCOHOLIC LIVER CIRRHOSIS
Abstract
Introduction. Alcoholic cirrhosis is one of the leading causes of morbidity and mortality worldwide. The pathophysiological mechanisms are not fully understood, treatment is expensive and often ineffective, the prognosis for life deteriorates significantly with the development of decompensation. The aim of the study was to assess the role of hepatocyte apoptosis in the development of acute-on-chronic liver failure (ACLF) in acutely decompensated alcoholic cirrhosis (ALC). Materials and methods. A total of 165 patients with ALC were examined: 94 (57.0%) men, 71 (43.0%) women aged 51.64±12.72 years; 92 (55.8%) — with simple acute decompensation (SAD) and 73 (44.2%) with ACLF. The presence of SAD, ACLF and their degrees were assessed using an online calculator https://www.clifresearch.com/ToolsCalculators.aspx). The ELISA method was used to determine the marker of hepatocyte apoptosis — fragments of cytokeratin-18 (FCK-18), using the TPS ELISA kit (Biotech, Sweden) for quantitative determination of cytokeratin 18 in serum. In healthy individuals, FCK-18 was 69.9±18.3 U/L. Results. The FCK-18 level in ACLF significantly exceeded that in SAD — 1702.8±602.09 U/L versus 913.78±412.39 U/L (p <0.05), exceeding the level in healthy individuals by 24 and 13 times, respectively. The hepatocyte necrosis index — aspartate aminotransferase (AST) — in ACLF also exceeded that in SAD, but the increase in AST compared to healthy individuals was only 6.3 in ACLF and 2.6 times in SAD. The FCK-18 level directly correlated with the activity of AST (r=0.59; p <0.01), ALT (r=0.49; p <0.05), CRP=0.46 (p <0.05), the degree of encephalopathy and vice versa — with the indices of the synthetic function of the liver. The level of FCK-18 increased in parallel with the severity of ACLF: at stage I it was 1465.72±705.13 U/L, and at stage III 1984.75±713.56 U/L (p <0.001). Conclusion. Hepatocyte apoptosis made a significant contribution to the development of decompensation of alcoholic liver cirrhosis, it was especially pronounced in acute on chronic liver failure. Cytokeratin-18 fragments as a biomarker of hepatocyte apoptosis should be used to identify patients at risk of developing acute in chronic liver failure.
References
Лазебник Л.Б., Голованова Е.В., Еремина Е.Ю. и др. Алкогольная болезнь печени (АБП) у взрослых. Экспериментальная и клиническая гастроэнтерология. 2020;174(2): 4–28. DOI: 10.31146/1682-8658-ecg-174-2-4-28.
Arroyo V., Moreau R., Kamath P.S. et al. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers. 2016;2:16041. DOI: 10.1038/nrdp.2016.41.
Claria J., Arroyo V., Moreau R. Roles of systemic inflammatory and metabolic responses in the pathophysiology of acute-on-chronic liver failure. JHEP Rep. 2023;5(9):100807. DOI: 10.1016/j.jhepr.2023.100807.
Denk H., Abuja P.M. & Zatloukal K. Mallory-Denk bodies and hepatocellular senescence: a causal relationship? VirchowsArch. 2024;484:637–644. DOI: 10.1007/s00428-024-03748-1.
Gustot Th., Rajiv Jalan R. Acute-on-chronic liver failure in patients with alcohol-related liver disease. J Hepatol. 2019;70(2):319–327. DOI: 10.1016/j.jhep.2018.12.008.
Lavallard V.J., Bonnafous S., Patouraux S., Saint-Paul M.C., Rousseau D., Anty R., Le Marchand-Brustel Y., Tran A., Gual P. Serum markers of hepatocyte death and apoptosis are non invasive biomarkers of severe fibrosis in patients with alcoholic liver disease. PLoS One. 2011;6(3):e17599. DOI: 10.1371/journal.pone.0017599.
Miyata T., Nagy L.E. Programmed cell death in alcohol-associated liver disease. Clin Mol Hepatol. 2020;26(4):618–625. DOI: 10.3350/cmh.2020.0142.
Moreau R., Jalan R., Gines P. et al. CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144:1426–1437. DOI: 10.1053/j.gastro.2013.02.042.
Rodina A.S., Shubina M.E., Kurbatova I.V., Topchieva L.V., Dudanova O.P. Hepatocytic Apoptosis and Immune Dysfunction in Decompensation of Alcoholic Liver Cirrhosis with Different Grades of Acute-on-Chronic Liver Failure. Bull Exp Biol Med. 2022;172(4):410–414. DOI: 10.1007/s10517-022-05404-7.
Seitz H.K., Bataller R., Cortez-Pinto H. et al. Alcoholic liver disease. Nat Rev Dis Primers. 2018;4(16). DOI: 10.1038/s41572-018-0014-7.
Tang D., Kang R., Berghe T.V., Vandenabeele P., Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29(5):347–364. DOI: 10.1038/s41422-019-0164-5.
Wang Y., Shi C., Guo J., Zhang Y., Gong Z. Distinct Types of Cell Death and Implications in Liver Diseases: An Overview of Mechanisms and Application. J Clin Transl Hepatol. 2023;11(6):1413–1424. DOI: 10.14218/JCTH.2023.00132.
Wu X., Fan X., Miyata T., Kim A., Cajigas-Du Ross C.K., Ray S., Huang E., Taiwo M., Arya R., Wu J., Nagy L.E. Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease. Annu Rev Pathol. 2023;18:411–438. DOI: 10.1146/annurev-pathmechdis-031521-030435.
Youssef E.M., Wu G.Y. Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance. J Clin Transl Hepatol. 2024;12(4):428–435. DOI: 10.14218/JCTH.2023.004.
