O. Fayura1, M. Abrahamovych1, O. Abrahamovych1, L. Fayura2
1Danylo Halytsky Lviv National Medical University
2Institute of Cell Biology of the National Academy of Sciences of Ukraine
Introduction. The course of liver cirrhosis (LC) is determined by the appearance and increase of the severity of syntropic comorbid lesions caused by the redox homeostasis disorders with the prooxidants system activity predominance and realizing its pathogenetic mechanism through the endothelial dysfunction. Due to the important role of oxidative stress among the etiologic and pathogenetic mechanisms of the LC onset and course, the pharmacological impact on it in the complex treatment deserves priority, being one of the main “targets”.
The aim of the study. To characterize the redox homeostasis index (RHI) as a criterion for the differentiated inclusion of antioxidants in the complex treatment of the patients with liver cirrhosis of different severity degree and evaluation of its effectiveness.
Materials and methods. The study was conducted in three steps. After obtaining the written consent to conduct the survey, 75 patients (23 women (30.7 %), 52 men (69.3 %), mean age – 47.2 ± 10.4 years) were enrolled in a randomized trial with preliminary stratification by the presence of LC. All of them underwent the complex clinical-laboratory-instrumental examination and inpatient treatment at Lviv Regional Hepatology Center. The state of redox homeostasis was evaluated by the malondialdehyde (MDA) and catalase (CAT) levels determining, and, on the basis of the received results, we proposed to calculate RHI. Reduced RHI (<7.6) was considered an indicator of redox homeostasis abnormality with a predominance in the prooxidant system, a value within 7.6-18.1 – a balance in the redox homeostasis system, increased (>18.1) – an indicator of the antioxidant system excessive activity.
The first step of our study was to determine the RHI to detect the disorders of redox homeostasis in patients with different severity degrees before the treatment, i.e. obtaining the information about the presence of patients with reduced, normal and increased values, which allows us to recommend the modification of standard complex treatment using antioxidants (medicine containing retinol palmitate (vitamin A) 100 000 MO and α-tocopherol acetate (vitamin E) 0.1 g – 1 capsule per os once a day after meals daily, ascorbic acid 0.05 g – 2 tablets per os once a day after meals daily, selenium 0,0002 g – 1 tablet per os once a day after meals daily for two months) only for patients with reduced RHI. The second step of the study was devoted to the determination of RHI after a course of complex differentiated treatment of the same patients with LC of varying severity. The third step of the study was to compare the RHI obtained after the course of complex differentiated treatment of patients with LC varying severity degrees with the values of the RHI prior to treatment. The actual material was processed on a personal computer in Exсel 2010, Statistica 6.0, RStudio v. 1.1.442 and R Commander v. 2.4-4. The results obtained were presented as Me [25.0 %; 75.0 %]. The difference was considered statistically significant if p < 0.05.
Results. The overwhelming majority of patients with LC (71 persons, representing 94.7 % of all those involved in the study) have disorders of redox homeostasis, among which patients with the signs of the prooxidant system prevalence and the antioxidant system activity attenuation are predominant (66 persons, accounting for 88.0 % of all those involved in the study), and the incidence of them significantly increases, as well as the value of RHI decreases with LC decompensation. Since redox homeostasis disorders with signs of attenuation of the antioxidant system activity have been diagnosed in the vast majority of patients with LC, and they determine to a large extent the features of the disease as well as the onset and severity increase of syntropic comorbid lesions, its medication adjustment is needed. RHI allows to determine the feasibility of including the antioxidants in their comprehensive treatment, as well as to determine its effectiveness, which depends on its indicators for the treatment and severity of liver cirrhosis and is the lowest in patients at the stage of decompensation of the disease. It is revealed that after the administering of the complex, differentiated standard treatment, modified by us, with the use of antioxidants RHI increases in patients with its primary decrease, which results in an improvement of the redox system state, which is the most pronounced in patients of class B, and the least – of class C by the criteria of C. G. Child – R. N. Pugh.
Conclusions. The redox homeostasis index is an important criterion for assessing the state of redox homeostasis in patients with liver cirrhosis of different severity, that allows to determine the feasibility of including the antioxidants in their complex treatment, as well as to determine its effectiveness, which is the lowest in patients with decompensated liver cirrhosis.
- Аbrahamovych МО, Аbrahamovych OO. Classification of liver cirrhosis: retrospective view on a problem and its modern solution taking into account the syntropic co- and polymorbid lesions of the patient. Med Transport Ukr. 2013;2:10-16 (Ukrainian).
- Abrahamovych MO, Abrahamovych OO, Fayura OP, Tolopko SYa, Ferko MR. Content of Some Endothotelium-Dependent Vasoactive Substances in the Blood of Patients, Depending on the Liver Cirrhosis Severity and the Organism’s Redox System State. Lviv Clinical Bulletin. 2019;4(28):19-27 (Ukrainian)) .
- Korolyuk MA, Ivanova LI, Mayorova IH, Tokarev VE. A method for determining the catalase activity. Laboratory Business. 1983;10:16-18 (Russian).
- Timirbulatov RR, Seleznev EI. A method of increasing the intensity of free radical oxidation of lipid-containing blood components and its diagnostic value. Laboratory Business. 1981;4:209-211 (Russian).
- Abdelazim SA, Darwish HA, Ali SA, Rizk MZ, Kadry MO. Potential antifibrotic and angiostatic impact of idebenone, carnosine and vitamin E in nano-sized titanium dioxide-induced liver injury. Cell Physiol Biochem. 2015;35:2402-2411.
- Abrahamovych O, Abrahamovych M, Tolopko S, Fayura O, Ferko M. Character and Frequency of the Variations of Coand Polymorbid Syntropic Extrahepatic Lesions and Their Dependence on the Hepatopulmonary Syndrome Severity Degree in Cirrhotic Patients. Georgian Medical News. 2016;11(260):34-41.
- Abrahamovych OO, Abrahamovych MO, Dovhan YP, Ferko MR, Tolopko SYa, Fayura OP. Ultrasound Doppler-flowmetric signes of portal hypertension in patients with liver cirrhosis, complicated with edematous-ascitic syndrome. Gastroenterologia Polska. 2013;20(4):139-142.
- Adikwu E, Deo O. Hepatoprotective effect of vitamin C (ascorbic acid). Pharmacol Pharm. 2013;4:84-92.
- Abudu N, Miller JJ, Attaelmannan M, Levinson SS. Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E. Clin Chim Acta. 2004;339:11-25.
- Bhogade RB, Suryakar AN, Joshi NG. Effect of vitamin E supplementation on oxidative stress in hemodialysis patients. Indian J Clin Biochem. 2008;23:233-237.
- Burk RF, Hill KE, Motley AK, Byrne DW, Norsworthy BK. Selenium deficiency occurs in some patients with moderate-to-severe cirrhosis and can be corrected by administration of selenate but not selenomethionine: a randomized controlled trial. Am J Clin Nutr. 2015;102:1126-1133.
- Burton GW, Ingold KU. Autooxidation of biological molecules. The antioxidant activity of vitamin E and related chain-breaking phenolic antioxidants in vitro. J Am Chem Soc. 1981;103:6472-6477.
- Cankurtaran M, Kav T, Yavuz B, Shorbagi A, Halil M, Coskun T, Arslan S. Serum vitamin-E levels and its relation to clinical features in nonalcoholic fatty liver disease with elevated ALT levels. Acta Gastroenterol Belg. 2006;69:5-11.
- Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol. 2014;20(25):8082-8091.
- Deger Y, Yur F, Ertekin A, Mert N, Dede S, Mert H. Protective effect of alpha-tocopherol on oxidative stress in experimental pulmonary fibrosis in rats. Cell Biochem Funct. 2007;25(6):633-637.
- Di Sario A, Candelaresi C, Omenetti A, Benedetti A. Vitamin E in chronic liver diseases and liver fibrosis. Vitam Horm. 2007;76:551-573.
- Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485-2490.
- Hill DB, Devalaraja R, Joshi-Barve S, Barve S, McClain CJ. Antioxidants attenuate nuclear factor-kappa B activation and tumor necrosis factor-alpha production in alcoholic hepatitis patient monocytes and rat Kupffer cells, in vitro. Clin Biochem. 1999;32:563-570.
- Hosomi A, Arita M, Sato Y, Kiyose C, Ueda T, Igarashi O et al. Affinity for α-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett. 1997;409:105-108.
- Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology. 1997;113:1069-1073.
- Kaur J, Shalini S, Bansal MP. Influence of vitamin E on alcohol-induced changes in antioxidant defenses in mice liver. Toxicol Mech Methods. 2010; 20:82-89.
- Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R. Characterization of mammalian selenoproteomes. Science. 2003;300:1439-1443.
- Mari M, Colell A, Morales A, VonMontfort C, Garcia‐Ruiz, Fernández‐Checa JC. Redox control of liver function in health and disease. Antioxid Redox Signal. 2010;12:1295‐
- Marí M, Morales A, Colell A, García‐Ruiz C, Fernández‐Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009;11:2685‐
- Masalkar PD, Abhang SA. Oxidative stress and antioxidant status in patients with alcoholic liver disease. Clin Chim Acta. 2005;355:61-65.
- Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr. 2003;22:18-35.
- Park JK, Ki MR, Lee HR, Hong IH, Ji AR, Ishigami A. Vitamin C deficiency attenuates liver fibrosis by way of up-regulated peroxisome proliferator-activated receptor-γ expression in senescence marker protein 30 knockout mice. Hepatology. 2010;51:1766-1777.
- Sies H, Stahl W. Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. Am J Clin Nutr. 1995;62:1315-1321.
- Singal AK, Jampana SC, Weinman SA. Antioxidants as therapeutic agents for liver disease. Liver Int. 2011;31(10):1432-1448.
- Tapiero H, Townsend DM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharm. 2003;57:134-144.
- Tinggi U. Selenium: its role as antioxidant in human health. Environ Health Prev Med. 2008;13:102-108.
- Weiskirchen R. Hepatoprotective and Anti-fibrotic Agents: It’s Time to Take the Next Step. Front Pharmacol. 2016;6:303.
- Yazar E, Konyalioglu S, Col R, Osman Birdane Y, Levent Bas A, Elmas M. Effects of vitamin E and prednisolone on some oxidative stress markers in endotoxemic rabbits. Revue Méd Vét, 2004;155(11):538-542.
- Zhang M, Song G, Minuk GY. Effects of hepatic stimulator substance, herbal medicine, selenium/vitamin E, and ciprofloxacin on cirrhosis in the rat. 1996;110:1150-1155.