Hepatocellular apoptosis in the mechanisms of progression of alcoholic liver cirrhosis

The aim - estimation of hepatocellular apoptosis (HA) in the alcoholic liver disease (ALC) progression from compensation to stable decompensation and acute-on-chronic liver failure (AСLF) and the diagnostic significance of cytokeratin-18 fragments (FCK-18) - marker of HA in different clinical variants of this disease. Materials and methods. 139 patients with ALC were examined: 17 - compensated ALC (men - 10-58,8%; 50.17±9.87 years), 65 - stable decompensated ALC (men - 33-50.8%; 52.13±12.52 years) and 57 with ACLF (men - 30-52,6%; 51.85±13.41 years). FCK-18 (TPS ELISA, Biotech, Sweden), TNF-α (Vector-Best, Russia) were determined, the CLIF-C-AD score and CLIF-C-ACLF score were calculated ((http://www.efclif.com/scientific-activity/score-calculators/clif-c-aclf). Results. The FCK-18 increased from the compensated stage 121.35±23.41 U/l to acute stable decompensation 913.78±312.39 U/l (p<0.001) and to ACLF - 1702.48±502.09 U/l (p<0.001). As the degree of HA, there was an increase in CRP - from 1.23 ± 0.05 mg / l to 20.37 ± 18.35 mg / l and 42.84 ± 19.74 mg / l (p < 0.01) and TNF-α - from 4.89 ± 1.35 pg / ml to 9.87 ± 3.12 pg / ml and 12.49 ± 3.08 pg / ml (p < 0.05), respectively, and organ failure developed - liver, kidney, cerebral, coagulation and circulatory. Short-term death occurred in 19 (33,3%) patients with ACLF. Conclusions. The role of HA in the mechanisms of ALC progression from compensated to stable decompensation and to ACLF and the diagnostic significance of the HA biomarker - FCK-18 in different clinical variants of ALC were shown.

liver cirrhosis, hepatocellular apoptosis, cytokeratin-18 fragments, acute-on-chronic liver failure

1. Lazebnik L. B., Golovanova E. V., Tarasova L. V., Krivosheev A. B., Sas E. I., Eremina E.Yu., Trukhan D. I., Hlynova O. V., Tsyganova Yu. V. Adult Alcoholic Liver Disease. Experimental and Clinical Gastroenterology. 2020;174(2):4-28. (In Russ.) doi: 10.31146/1682-8658-ecg-174-2-4-28.@@ Лазебник Л. Б., Голованова Е. В., Тарасова Л. В., Кривошеев А. Б., Сас Е. И., Еремина Е. Ю., Трухан Д. И., Хлынова О. В., Цыганова Ю. В. 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.

2. Ivashkin V. T., Maevskaya M. V., Zharkova M. S. et al. Clinical Recommendations of the Russian Scientific Liver Society and Russian Gastroenterological Association on Diagnosis and Treatment of Liver Fibrosis, Cirrhosis and Their Complications.Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2021;31(6):56-102. doi: 10.22416/1382-4376-2021-31-6-56-102.@@ Ивашкин В. Т., Маевская М. В., Жаркова М. С. и др. Клинические рекомендации Российского общества по изучению печени и Российской гастроэнтерологической ассоциации по диагностике и лечению фиброза и цирроза печени и их осложнений. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2021;31(6):56-102. doi: 10.22416/1382-4376-2021-31-6-56-102.

3. Jophlin L. L., Singal A. K., Bataller R., Wong R. J., Sauer B. G., Terrault N. A., Shah V. H. ACG Clinical Guideline: Alcohol-Associated Liver Disease. Am J Gastroenterol. 2024. 1;119(1):30-54. doi: 10.14309/ajg.0000000000002572.

4. Cholankeril G., Ahmed A. Alcoholic Liver Disease Replaces Hepatitis C Virus Infection as the Leading Indication for Liver Transplantation in the United States. Clin Gastroenterol Hepatol. 2018;16(8):1356-1358. doi: 10.1016/j.cgh.2017.11.045.

5. Julien J., Ayer T., Bethea E. D., Tapper E. B., Chhatwal J. Projected prevalence and mortality associated with alcohol-related liver disease in the USA, 2019-40: a modelling study. Lancet Public Health. 2020 Jun;5(6): e316-e323. doi: 10.1016/S2468-2667(20)30062-1.

6. Kumar R., Kumar S., Prakash S. S.Compensated liver cirrhosis: Natural course and disease-modifying strategies. World J Methodol. 2023;13(4):179-193. doi: 10.5662/wjm.v13.i4.179.

7. 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(7):1426-37, 1437.e1-9. doi: 10.1053/j.gastro.2013.02.042.

8. Trebicka J., Fernandez J., Papp M. et al.; PREDICT STUDY group of the EASL-CLIF Consortium. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol. 2020;73(4):842-854. doi: 10.1016/j.jhep.2020.06.013.

9. D’Amico G., Bernardi M., Angeli P. Towards a new definition of decompensated cirrhosis. J Hepatol. 2022;76(1):202-207. doi: 10.1016/j.jhep.2021.06.018.

10. Gustot T., Fernandez.J, Garcia E., Morando F., Caraceni P., Alessandria C. et al. CANONIC Study Investigators of the EASL-CLIF Consortium. Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology. 2015;62(1):243-52. doi: 10.1002/hep.27849.

11. Clària J., Stauber R. E., Coenraad M. J. et al. CANONIC Study Investigators of the EASL-CLIF Consortium and the European Foundation for the Study of Chronic Liver Failure (EF-CLIF). Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology. 2016;64(4):1249-64. doi: 10.1002/hep.28740.

12. Laleman W., Claria J., Van der Merwe S., Moreau R., Trebicka J. Systemic Inflammation and Acute-on-Chronic Liver Failure: Too Much, Not Enough. Can J Gastroenterol Hepatol. 2018;2018:1027152. doi: 10.1155/2018/1027152.

13. Cao L., Quan X. B., Zeng W. J., Yang X. O., Wang M. J. Mechanism of Hepatocyte Apoptosis. J Cell Death. 2016;9:19-29. doi: 10.4137/JCD.S39824.

14. Jones A. B., Gores G. J. Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine. Am Journal of Physiology. 1997; 273 (6): 1174-1188. doi: 10.1152/ajpgi.1997.273.6.G1174.

15. Macdonald S., Andreola F., Bachtiger P. et al. Cell death markers in patients with cirrhosis and acute decompensation. Hepatology. 2018;67(3):989-1002. doi: 10.1002/hep.29581.

16. Adebayo D., Morabito V., Andreola F. et al. Mechanism of cell death in acute-on-chronic liver failure: a clinico-pathologic-biomarker study. Liver Int. 2015;35(12):2564-74. doi: 10.1111/liv.12850.

17. 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. Bulletin of Experimental Biology and Medicine. 2021; 172 (10):416-421. (In Russ.) doi: 10.47056/0365-9615-2021-172-10-416-42.@@ Родина А. С., Шубина М. Э., Курбатова И. В., Топчиева Л. В., Дуданова О. П. Гепатоцитарный апоптоз и иммунная дисфункция при декомпенсации алкогольного цирроза печени с разными степенями острой на фоне хронической печёночной недостаточности. Бюллетень экспериментальной биологии и медицины. 2021;172 (10): 416-421. doi: 10.47056/0365-9615-2021-172-10-416-42.

18. Guicciardi M. E., Gores G. J. Apoptosis: a mechanism of acute and chronic liver injury. Gut. 2005;54(7):1024-33. doi: 10.1136/gut.2004.053850.

19. Schwabe R. F., Luedde T. Apoptosis and necroptosis in the liver: a matter of life and death. Nat Rev Gastroenterol Hepatol. 2018;15(12):738-752. doi: 10.1038/s41575-018-0065-y.

20. Gowda S., Desai P. B., Hull V. V., Math A. A., Vernekar S. N., Kulkarni S. S. A review on laboratory liver function tests. Pan Afr Med J. 2009. 22;3:17.

21. McGill M. R. The past and present of serum aminotransferases and the future of liver injury biomarkers. EXCLI J. 2016;15:817-828. doi: 10.17179/excli2016-800.

22. Aizawa S., Brar G., Tsukamoto H. Cell Death and Liver Disease. Gut Liver. 2020;14(1):20-29. doi: 10.5009/gnl18486.

23. Huang L., Liu J., Bie C., Liu H., Ji Y., Chen D., Zhu M., Kuang W. Advances in cell death - related signaling pathways in acute-on-chronic liver failure. Clin Res Hepatol Gastroenterol. 2022;46(2):101783. doi: 10.1016/j.clinre.2021.101783.

24. Kondo T., Macdonald S., Engelmann C. et al. The role of RIPK1 mediated cell death in acute on chronic liver failure. Cell Death Dis. 2021;13(1):5. doi: 10.1038/s41419-021-04442-9.

25. Osna N. A., Tikhanovich I., Ortega-Ribera M. et al. Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression. Biomolecules. 2024;14(4):404. doi: 10.3390/biom14040404.

26. Lu W., Yan L., Peng L., Wang X., Tang X., Du J. et al. Efficacy and safety of mesenchymal stem cell therapy in acute on chronic liver failure: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther. 2025; 16: 197. doi: 10.1186/s13287-025-04303-8.