Proinflammatory cytokines VEGFA, IL-6, IL-8 as markers of hepatotoxicity after COVID-19

The mechanism of hepatocellular liver damage after COVID-19 is a multifactorial process. The most widely discussed causes are cytolytic liver damage due to the inflammatory response after COVID-19, drug-induced hepatotoxicity and direct cytotoxic effect of the virus. There are observations that SARSCoV-2 infection causes hepatitis B virus reactivation, but little has been described about the interaction between hepatitis C virus and SARS-CoV-2. The course of coronavirus infection is associated with marked expression of proinflammatory cytokines, participants in the multisystem inflammatory response, IL-1β, IL-6, IL-8, IL-18, MCP-1, TNFα, which contribute significantly to the observed early and late liver function impairment. The aim of the study was to evaluate the role of proinflammatory cytokines (VEGFA, IL-8, IL-6, MCP-1, TNFα, IL-18) as additional markers of hepatotoxicity after COVID-19. The study was performed between March and August 2022. Patients were divided into 2 groups: Group 1 – with increased aminotransferases against the background of treatment from COVID-19 and/or in the following 3-6 months after the disease without viral liver damage (n = 42), Group 2 – patients with co-infection (chronic viral hepatitis C (HCV) and COVID-19 (n = 26). The levels of cytokines – VEGF-A, IL-6, IL-8, MCP-1, IL-18, TNFα in blood serum were estimated by enzyme immunoassay method. Statistical analysis was performed using StatTech v. 3.1.4. The results of the study revealed a comparable increase in the level of transaminases and C-reactive protein in both groups, significantly different from the reference values. Direct correlations of moderate strength (linear Spearman correlation) were found between the following cytokines: TNFα-MCP-1 (R = 0.559; p = 0.001), TNFα-VEGFA (R = 0.400; p = 0.002), TNFα-IL-6 (R = 0.503; p = 0.001). We diagnosed a significant increase in serum VEGFA levels in group 1 patients (hepatotoxicity after COVID-19) (Me (Q_0.25-Q_0.75): 522 (250 to 1002), p = 0.001) and in group 2 patients (HCV + COVID-19) (Me 1196, Q_0.25-Q_0.75: (73 to 432). Similar trend with the level of IL-6, IL-8, exceeding the values of cytokines in healthy donors and significantly higher than in group 2 patients. Identified correlations between inflammatory cytokines prove unidirectional changes in the functioning of the regulatory network controlling immune virus-induced reactions.

1. Alqahtani S.A., Schattenberg J.M. Liver injury in COVID-19: The current evidence. United European Gastroenterol J., 2020, Vol. 8, no. 5, pp. 509-519.

2. Bzeizi K., Abdulla M., Mohammed N., Alqamish J., Jamshidi N., Broering D. Effect of COVID-19 on liver abnormalities: a systematic review and meta-analysis. Sci. Rep., 2021, Vol. 11, no. 1, 10599. doi: 10.1038/s41598-021-89513-9.

3. Cabibbo G., Rizzo G.E.M., Stornello C., Craxì A. SARS-CoV-2 infection in patients with a normal or abnormal liver. J. Viral Hepat., 2021, Vol. 28, no. 1, pp. 4-11.

4. Cao Y. The impact of the hypoxia-VEGF-vascular permeability on COVID-19-infected patients. Exploration (Beijing), 2021, Vol. 1, no. 2, 20210051. doi: 10.1002/EXP.20210051.

5. Devaux C.A., Lagier J.C. Unraveling the underlying molecular mechanism of ‘Silent Hypoxia’ in COVID-19 patients suggests a central role for angiotensin II modulation of the AT1R-hypoxia-inducible factor signaling pathway. J. Clin. Med., 2023, Vol. 12, no. 6, 2445. doi: 10.3390/jcm12062445.

6. Dufour J.F., Marjot T., Becchetti C., Tilg H. COVID-19 and liver disease. Gut, 2022, Vol. 71, no. 11, pp. 2350-2362.

7. Kruse R.L. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Res., 2020, Vol. 9, 72. doi: 10.12688/f1000research.22211.2.

8. Lu X.H., Yang J.L., Deng K. COVID-19 Patients With Hepatitis B Virus Infection. Am. J. Gastroenterol., 2021, Vol. 116, no. 6, pp. 1357-1358.

9. Ozkurt Z, Çınar Tanrıverdi E. COVID-19: Gastrointestinal manifestations, liver injury and recommendations. World J. Clin. Cases, 2022, Vol. 10, no. 4, pp. 1140-1163.

10. Sodeifian F., Seyedalhosseini Z.S., Kian N., Eftekhari M., Najari S., Mirsaeidi M., Farsi Y., Nasiri M.J. DrugInduced Liver Injury in COVID-19 Patients: A Systematic Review. Front. Med. (Lausanne), 2021, Vol. 8, 731436. doi: 10.3389/fmed.2021.731436.

11. Wong G.L., Wong V.W., Thompson A., Jia J., Hou J., Lesmana C.R.A., Susilo A., Tanaka Y., Chan W.K., Gane E., Ong-Go A.K., Lim S.G., Ahn S.H., Yu M.L., Piratvisuth T., Chan H.L.; Asia-Pacific Working Group for Liver Derangement during the COVID-19 Pandemic. Management of patients with liver derangement during the COVID-19 pandemic: an Asia-Pacific position statement. Lancet Gastroenterol. Hepatol., 2020, Vol. 5, no. 8, pp. 776-787.