The importance of single-nucleotide gene polymorphisms in the formation of liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis C

Background. Chronic hepatitis C is an urgent health problem in Russia and in the world. The medical and socio-economic significance of this pathology is associated with the steady development and progression of fibrosis and cirrhosis of the liver, as well as hepatocellular cancer. This review article reveals the importance of single-nucleotide gene polymorphisms in the formation of liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis C.

Objective. To identify the importance of genetic predictors of the development and progression of fibrosis and cirrhosis of the liver, as well as hepatocellular cancer in patients with chronic hepatitis C, including those who have achieved a stable virological response against the background of antiviral therapy with direct antiviral drugs.

Materials and methods. Current scientific publications of domestic and foreign authors, the results of clinical studies devoted to the study of the clinical significance of various single-nucleotide gene polymorphisms in patients with chronic hepatitis C were used as research material. During the work on the article, an analysis of the literature was carried out, generalization and structuring of the data obtained, including the formation of tables, discussion of the research topic with the formulation of conclusions and outlining the prospects for further study of this topic.

Conclusion. Currently, taking into account the high effectiveness of antiviral therapy for chronic hepatitis C with direct antiviral drugs, the quality of life of a patient who has achieved a stable virological response is determined by the presence of liver fibrosis and the risk of cirrhosis and hepatocellular liver cancer. It is becoming important to find a personalized approach to such patients, which allows us to identify predictors of the formation of undesirable outcomes of chronic hepatitis C. Single nucleotide polymorphisms of genes are a promising direction in the study and application as genetic markers of various pathological conditions and diseases.

1. Kamp W. M., Sellers C. M., Stein S., et al. Direct-acting antivirals improve overall survival in interventional oncology patients with hepatitis C and hepatocellular carcinoma. J. Vasc. Intervent. Radiol. 2020; 31: 953-960.

2. Polaris Observatory HCV Collaborators. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study. Lancet Gastroenterol. Hepatol. 2022; 7: 396-415.

3. Malov S. I. Clinical-pathogenetic and prognostic value of biomarkers in hepatitis c and associated diseases. Dissertation for a thesis for the degree of Doctor of medical sciences. 2022. P. 25-26. (In. Russ.)

4. Ooka Y., Miho K. Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection. Hepatol. Int. 2018; 12: 523-530.

5. Mohamed Darwish Ahmed Abd Alla, Reham M. Dawood, Hassan Abd El-Hafeth Rashed, et al. Treatment of hepatitis C virus infection with direct-acting antivirals plus ribavirin eliminates viral RNA from peripheral blood mononuclear cells and reduces virologic relapse in diverse hepatic parenchymal changes. Arch Virol. 2021; 166 (4): 1071-1081. DOI: 10.1007/s00705-021-04969-4.

6. Ashraf O. Abdelaziz, Mohamed M. Nabil, Ahmed H. Abdelmaksoud, Hen, et al. De-novo versus recurrent hepatocellular carcinoma following direct-acting antiviral therapy for hepatitis C virus. Eur J Gastroenterol Hepatol. 2018; 30 (1): 39-43. DOI: 10.1097/MEG.0000000000001004.

7. Innes H., Jepsen P., McDonald S., et al. Performance of models to predict hepatocellular carcinoma risk among UK patients with cirrhosis and cured HCV infection. JHEP Rep. 2021; 6 (3): 100384.

8. Llovet J. M., Kelley R. K., Villanueva A., et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 1 (7): 6.

9. McGlynn K. A., Petrick J. L., El-Serag H. B. Epidemiology of hepatocellular carcinoma. Hepatology. 2021; 1 (73): 4-13.

10. Sagnelli E., Macera M., Russo A., et al. Epidemiological and etiological variations in hepatocellular carcinoma. Infection. 2020; 1 (48): 7-17.

11. Watanabe T., Tokumoto Y., Joko K., et al. Sex difference in the development of hepatocellular carcinoma after direct-acting antiviral therapy in patients with HCV infection. J Med Virol. 2020. DOI: 10.1002/jmv.25984.

12. Baatarkhuu O., Gerelchimeg T., Munkh-Orshikh D., et al. Epidemiology, genotype distribution, prognosis, control, and management of viral hepatitis B, C, D, and hepatocellular carcinoma in Mongolia. Euroasian J Hepatogastroenterol. 2018; 1 (8): 57-62.

13. Russo F. P., Zanetto A., Pinto E., et al. Hepatocellular carcinoma in chronic viral hepatitis: Where do we stand? Int J Mol Sci. 2022; 1 (23): 500.

14. Kanwal F., Kramer J. R., Asch S. M., et al. Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents. Hepatology. 2020; 1 (71): 44-55.

15. Ogawa E., Nomura H., Nakamuta M., et al. Development of Hepatocellular Carcinoma in Patients Aged 75-84 Years With Chronic Hepatitis C Treated With Direct-Acting Antivirals. J Infect Dis. 2022; 226 (3): 431-440. DOI: 10.1093/infdis/jiaa359.

16. Petrick J. L., Florio A. A., Znaor A., et al. International trends in hepatocellular carcinoma incidence, 1978-2012 . Int J Cancer. 2020; 2 (147): 317-330.

17. Tashpolotova A. Sh., Suranbaeva G. S. The role of viral hepatitis in the development of liver cirrhosis. Mezhdunarodnyi zhurnal prikladnykh i fundamentalnykh issledovanii. 2019; 7: 68-72. (In Russ.)

18. Ioannou G. N., Beste L. A., Green P. K., et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology. 2019; 5 (157): 1264-1278.

19. Muzica C. M., Stanciu C., Huiban L., et al. Hepatocellular carcinoma after direct-acting antiviral hepatitis C virus therapy: A debate near the end. World J Gastroenterol. 2020; 43 (26): 6770-6781.

20. Tanaka Y., Ogawa E., Huang C. F., et al. HCC risk post-SVR with DAAs in East Asians: Findings from the REAL-C cohort. Hepatol Int. 2020; 6 (14): 1023-1033.

21. Pons M., Rodríguez-Tajes S., Esteban J. I., et al. Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals. J Hepatol. 2020; 3 (72): 47-480.

22. Bayart J. L., Mairesse A., Gruson D., et al. Analytical performances and biological variation of PIVKA-II (des-y-carboxy-prothrombin) in European healthy adults. Clin Chim Acta. 2020; 509: 264-267.

23. Koike K., Tsutsumi T. The oncogenic role of hepatitis C virus. Recent Results Cancer Res. 2021; 217: 91-105.

24. Virzì A., Gonzalez-Motos V., Tripon S., et al. Profibrotic signaling and HCC risk during chronic viral hepatitis: Biomarker development. J Clin Med. 2021; 5 (10): 977.

25. Shcherbo S. N., Tishenko A. L. Shcherbo D. S., et al. Genetic predisposition and resistance to certain infectious diseases. I. AIDS. Medical alphabet. 2019; 2 (23): 6-10. (In Russ.)

26. Dawood R. M., El-Meguid M. A., Salum G. M., et al. Key Players of Hepatic fibrosis. J Interf Cytokine Res. 40: 472-489. https://doi.org/10.1089/jir.2020.0059.

27. Ma J., Liu Y. C., et al. TGF-beta1polymorphism 509 C>T is associated with an increased risk for hepatocellular carcinoma in HCV-infected patients. Genet Mol Res. 2015; 14: 4461-4468.

28. Jeng J. E., Tsai J. F., et al. Tumor necrosis factor-alpha polymorphism is associated with advanced hepatic fibrosis and higher risk for hepatocellular carcinoma. Neoplasia. 2007; 9: 987-992.

29. Bouzgarrou N., Hassen E., et al. Combined analysis of interferon-gamma and interleukin-10 gene polymorphisms and chronic hepatitis C severity. Hum Immunol. 2009; 70: 230-236.

30. Fakhraie G., Parvini F., et al. Association of IL-10 gene promoter polymorphisms with susceptibility to pseudoexfoliation syndrome, pseudoexfoliative and primary open-angle glaucoma. BMC Med Genet. 2020; 21: 32.

31. Noureddin M., Wright E. C., et al. Association of IL28B genotype with fibrosis progression and clinical outcomes in patients with chronic hepatitis C: a longitudinal analysis. Hepatology. 2013; 58: 1548-1557.

32. Simili A., Mazzella G., Ravaioli F., et al. Interleukin 28 polymorphisms and hepatocellular carcinoma development after direct acting antiviral therapy for chronic hepatitis C. J Gastrointestin Liver Dis. 2019; 4 (28): 449-456.

33. Giannitrapani .L, Soresi M., et al. Genetic association of interleukin-6 polymorphism (-174 G/C) with chronic liver diseases and hepatocellular carcinoma. World J Gastroenterol. 2013; 19: 2449-2455.

34. Huang H., Shiffman M. L., Friedman S., et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology. 2007; 46: 297-306. https://doi.org/10.1002/hep.21695.

35. Bulatova I. A., Shevlyukova T. P., Shchekotova A. P., et al. Presence of CAT genetic markers as an indicator of accelerated rate of liver fibrosis progression in patients with chronic hepatitis. Experimental and Clinical Gastroenterology. 2021; 189 (5): 39-43. (In Russ.) DOI: 10.31146/1682-8658-ecg-189-5-39-43. (In. Russ.)

36. Dawood R. M., Salum G. M. Development of a gene signature for predicting cirrhosis risk score of chronic liver disease associated with HCV infection in Egyptians. Microb Pathog. 2021; 153: 104805. DOI: 10.1016/j.micpath.2021.104805.

37. Galal A. S., Reham M. Dawood, Mostafa K. E., et al. Recognition of 7 genes signature (Cirrhosis Risk Score) in the diagnosed non-responders to DAAs therapy by intra-PBMCs nested HCV RNA PCR. J Genet Eng Biotechnol. 2023; 21 (1): 89. DOI: 10.1186/s43141-023-00544-3.