Hepatosplenomegaly in liver cirrhosis is caused by reactive oxygen species formation, an increase in apoptosis and autophagy, and pronounced autoimmune reactions

  • E. M. Klimova Zaycev V. T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine
  • L. A. Drozdova Zaycev V. T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine
  • O. V. Lavinska V. N. Karazin Kharkiv National University
  • E. A. Bychenko Zaycev V. T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine
  • Y. H. Kot
  • T. I. Kordon
Keywords: hepatosplenomegaly; immunoreactivity; complement system component; phagocytic cell; autoantibodies


Various factors of infectious and toxic genesis can lead to the liver cirrhosis, often accompanied by complications such as recurrent bleeding due to portal hypertension against the background of hepatosplenomegaly. Metabolic changes and disturbances in immunoreactivity occur in the liver and spleen. To substantiate the choice of personalized treatment tactics for patients with hepatosplenomegaly, we investigated individual metabolic predictors and immunopathological processes in patients with: liver cirrhosis and hepatitis B (HBV) and/or hepatitis C (HCV) viruses (I group, n = 52); with herpes viruses CMV (cytomegalovirus) and EBV (Epstein-Barr virus) (II group, n = 48), and with splenomegaly and frequent recurrent bleeding associated with hereditary enzymopathies (III group, n = 15). We used the methods of immunoturbidimetry; enzyme immunoassay; light, fluorescence and confocal microscopy. In group I (HBV/HCV), we revealed a decrease in the C4 component; a significant increase in the phagocytic index and phagocytic number, a reduced number of active phagocytes and the digestion index; a decrease in the IL-1β content and an increase in IL-18 and IL-6. In group II (CMV/EBV), we revealed a high activity of the C3 and a low activity of the C4 component against the background of a high level of ROS in neutrophils; the antineutrophil antibodies (ANCA) formation in 85.7% of patients (71.4% –perinuclear antibodies (pANCA) to myeloperoxidase; 14.3% – cytoplasmic antibodies (CANCA) to proteinase 3). Also, in group II, an increased level of pro-inflammatory cytokines IFN-γ, IL-1β, TNF-α, IL-18 and anti-inflammatory IL-6 was detected. Changes in links of immunity in II group led to the formation of autoimmune reactions in 64.7% of patients, which was expressed in the development of a broad range of antinuclear antibodies ANA (11 specificities, including ANA to chromatin and chromatin-associated proteins, to proteins cytoskeleton, enzymes and enzyme complexes). In group III, we revealed a low absorption capacity of neutrophils, a high frequency of antineutrophil antibodies pANCA occurrence and cANCA (in 67.2% of the examined), and low concentration of TNF-α. The developed model of the stepwise change of immunological markers makes it possible to substantiate the choice of a complex targeted treatment, including antiviral and immunotropic therapy.


Ahsan, H., Ali, A., & Ali, R. (2003). Oxygen free radicals and systemic autoimmunity. Clinical and Experimental Immunology, 131(3), 398–404.

Alimova, L. A., Begmanov, S. A., Nigmatov, N. N., & Abidova, N. A. (2015). Nekotorye aspekty razvitiya infekcionno-allergicheskogo i toksicheskogo gepatita i cirroza pecheni [Some aspects of the development of infectious-allergic and toxic hepatitis and liver cirrhosis]. Bulletin of Novosibirsk State Pedagogical University, 5(1), 80–87 (in Russian).

Bedard, K., & Krause, K.-H. (2007). The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiological Reviews, 87(1), 245–313.

Bhasin, D. K., & Malhi, N. J. S. (2002). Variceal bleeding and portal hypertension: Much to learn, much to explore. Endoscopy, 34(2), 119–128.

Borisov, A. E., & Kashchenko, V. A. (2009). Cirroz pecheni i portal’naya gipertenziya [Cirrhosis of the liver and portal hypertension]. Sintez-Buk, Saint Petersburg (in Russian).

Box, H. C., Dawidzik, J. B., & Budzinski, E. E. (2001). Free radical-induced double lesions in DNA. Free Radical Biology and Medicine, 31(7), 856–868.

Brilland, B., Garnier, A. S., Chevailler, A., Jeannin, P., Subra, J.-F., & Augusto, J.-F. (2020). Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside. Autoimmunity Review, 19(1), 102424.

Caballero, F., Fernandez, A., Matias, N., Martinez, L., Fucho, R., Elena, M., Caballeria, J., Morales, A., Fernandez-Checa, J., & Garcia-Ruiz, C. (2010). Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: Impact on mitochondrial S-adenosyl-L-methionine and glutathione. The Journal of Biological Chemistry, 285(24), 18528–18536.

Cadet, J., Bellon, S., Berger, M., Bourdat, A.-G., Douki, T., Duarte, V., Frelon, S., Gasparutto, D., Muller, E., Ravanat, J.-L., & Sauvago, S. (2002). Recent aspects of oxidative DNA damage: Guanine lesions, measurement and substrate specificity of DNA repair glycosylases. Biological Chemistry, 383(6), 933–943.



Cooke, M. S., Evans, M. D., Dizdaroglu, M., & Lunec, J. (2003). Oxidative DNA damage: Mechanisms, mutation, and disease. The Journal of the Federation of American Societies for Experimental Biology, 17, 1195–1214.


De Oliveira, I. M. X., & da Silva, R. S. U. (2019). Rheumatological manifestations associated with viral hepatitis B or C. Revista da Sociedade Brasileira de Medicina Tropical, 2, e20180407.

Dixit, K., & Ali, R. (2001). Antigen binding characteristics of antibodies induced against nitric oxide modified plasmid DNA. Biochimica et Biophysica Acta, 1528(1), 1–8.

Elbim, C., Monceaux, V., Mueller, Y. M., Lewis, M. G., Francois, S., Diop, O., Akarid, K., Hurtrel, B., Gougerot-Pocidalo, M.-A., Levy, Y., Katsikis, P. D., & Estaquier, J. (2008). Early divergence in neutrophil apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates. Journal of Immunology, 181(12), 8613–8623.

Ellmark, P., Furebring, C., & Borrebaeck, C. A. (2003). Pre-assembly of the extracellular domains of CD40 is not necessary for rescue of mouse B cells from anti-immunoglobulin M-induced apoptosis. Immunology, 108(4), 452–457.

Ferreira, C. R., & Gahl, W. A. (2017). Lysosomal storage diseases. Тranslational Science of Rare Diseases, 2, 1–71.

Fischer, R., Baumert, T., & Blum, H. E. (2007). Hepatitis C virus infection and apoptosis. World Journal of Gasrtoenterology, 13, 4865–4872.

Gorchakov, A. M., Kruchinsky, N. G., Gorchakova, F. T., & Korosteleva, I. V. (2003). Metod kompleksnoj ocenki fagocitarnoj aktivnosti nejtrofilov krovi [Method of comprehensive assessment of the phagocytic activity of blood neutrophils]. Institute of Environmental and Professional Pathology, Minsk (in Russian).

Grechanina, E. Y., Grechanina, Y. B., & Goldfarb, I. G. (2004). Hromosomnyj polimorfizm i metabolicheskie narusheniya – prichinno-sledstvennye svyati [Chromosomal polymorphism and metabolic disorders – cause-and-effect relations]. Ultrasound Perinatal Diagnostics, 17, 38–43 (in Russian).

Kanto, T. (2008). Virus associated innate immunity in liver. Frontiers in Bioscience, 13, 6183–6192.

Klimova, O. M., Kordon, T. I., Smachilo, R. M., Beloziorov, I. V., Bichenko, K. O., Merezhko, O. S., & Kudrevich, O. M. (2019). Diferencіal’na dіagnostika і korekcіya metabolіchnih ta іmunologichnih porushen’ u hvorih z cirozom pechіnki, uskladnenim gepatosplenomegalіjeyu ta portal’noyu gіpertenzіjeyu [Differential diagnosis and correction of metabolic and immunological disorders in ailments with liver cirrhosis, accelerating hepatosplenomegaly and portal hypertension]. Actual Problems of Current Medicine, 41, 31–41 (in Russian).

Knight, R. A., & Melino, G. (2011). Cell death in diseаse: From 2010 onwards. Cell Death and Disese, 2, e202.

Kolter, T., & Sandhoff, K. (2005). Principles of lysosomal membrane digestion: Stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annual Review of Cell and Developmental Biology, 21, 81–103.

Lallemand-Breitenbach, V., & de The, H. (2018). PML nuclear bodies: From architecture to function. Current Opinion in Cell Biology, 52, 154–161.

Lam, G. Y., Huang, J., & Brumell, J. H. (2010). The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Seminars in Immunopathology, 32(4), 415–430.

Lieber, C. S. (2002). S-adenosyl-L-methionine: its role in the treatment of liver disorders. The American Journal of Clinical Nutrition, 76(5), 1183–1187.

Lu, S. C., Ramani, K., Ou, X., Lin, M., Yu, V., Ko, K., Park, R., Bottiglieri, T., Tsukamoto, H., Kanel, G., French, S. W., Mato, J. M., Moats, R., & Grant, E. (2009). S‐adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model. Hepatology, 50, 462–471.

Nilsson, B., & Nilsson, E. K. (2012). Complement diagnostics: Concepts, indications, and practical guidelines. Clinical and Developmental Immunology, 2012, 962702.

Panasiuk, A., Prokopowicz, D., Zak, J., & Wysocka, J. (2003). Peripheral blood T, B, and NK cells in relation to histological hepatitis activity and fibrosis stage in chronic hepatitis C. Hepato-Gastroenterology, 50(49), 178–182.

Park, B. H., Fikrig, S. M., & Smithwick, E. M. (1968). Infection and nitroblue-tetrazolium reduction by neutrophils: A diagnostic acid. Lancet, 2, 532–534.

Phaniendra, A., Jestadi, D. B., & Periyasamy, L. (2015). Free radicals: Properties, sources, targets, and their implication in various diseases. Indian Journal of Clinical Biochemistry, 30(1), 11–26.

Robinson, M. W., Harmon, C., & O’Farrelly, C. (2016). Liver immunology and its role in inflammation and homeostasis. Cellular and Molecular Immunology, 13, 267–276.

Scherer, M., & Stamminger, T. (2016). Emerging role of PML nuclear bodies in innate immune signaling. Journal of Virology, 90(13), 5850–5854.

Simpson, W. L., Hermann, G., & Balwani, M. (2014). Imaging of gaucher disease. World Journal of Radiology, 6(9), 657–668.

Spiller, O. B., Morgan, B. P., Tufaro, F., & Devine, D. V. (1996). Altered expression of host-encoded complement regulators on human cytomegalovirus-infected cells. European Journal of Immunology, 26(7), 1532–1538.

Tkachenko, O. Y., Lapin, S. V., Mazing, A. V., Totolian, & Areg, A. (2020). Russkoyazychnaya adaptaciya mezhdunarodnoj nomenklatury tipov svecheniya yadra i citoplazmy kletki (ICAP) dlya standartizacii vyyavleniya antinuklearnogo faktora [Russian-speaking adaptation of the international nomenclature of luminance types of the nucleus and cell cytoplasm (ICAP) for standardization of antinuclear factor detection]. Medical Immunology, 22(6), 1195–1214 (in Russian).

Voitsekhovsky, V. V., & Goborov, N. D. (2019). Cplenomegaliya v klinicheskoj praktike [Splenomegaly in clinical practice]. Amur Medical Journal, 2(26), 61–77 (in Russian).

Zimran, A., Sorge, J., Gross, E., Kubitz, M., West, C., & Beutler, E. (1990). A glucocerebrosidase fusion gene in gaucher disease. Implications for the molecular anatomy, pathogenesis, and diagnosis of this disorder. The Journal of Clinical Investigation, 85(1), 219–222.

How to Cite
Klimova, E. M., Drozdova, L. A., Lavinska, O. V., Bychenko, E. A., Kot, Y. H., & Kordon, T. I. (2021). Hepatosplenomegaly in liver cirrhosis is caused by reactive oxygen species formation, an increase in apoptosis and autophagy, and pronounced autoimmune reactions . Regulatory Mechanisms in Biosystems, 12(3), 408-418. https://doi.org/10.15421/022156

Most read articles by the same author(s)