Skrypnyk R. Interrelation of liver and intestinal injury in patients with chronic lymphoproliferative diseases and methods of their correction

The dissertation is devoted to the methods of diagnostics and prevention of liver and intestinal lesions in the setting of chemotherapy of chronic lymphoproliferative diseases, taking into account the main pathogenetic mechanisms of their formation and the type of hemoblastosis. The purpose of the study is to substantiate a differentiated approach to the prevention of liver, small and large intestine lesions in the setting of chemotherapy for chronic lymphoproliferative diseases based on experimental and clinical studies of the pathogenetic mechanisms of their formation. A clinical, prospective, open-label, controlled study was conducted, which included 75 patients with chronic lymphoproliferative diseases who were treated in the hematology department of the Municipal Institution "M.V. Sklifosovsky Poltava Regional Clinical Hospital of the Poltava Regional Council" from 2018 to 2022. We evaluated the values of biochemical blood test, oxidant-antioxidant state (thiobarbituric acid concentration, catalase activity in blood serum), arginine/citrulline cycle (arginine, citrulline content, arginase activity in blood serum). The experimental part of the study was conducted on 60 white nonlinear rats. The modeling of non-alcoholic steatohepatitis, doxorubicin-induced liver, small and large intestine lesions in rats with non-alcoholic steatohepatitis was performed, followed by the evaluation of laboratory and structural changes in liver, small and large intestine tissues. According to the results of the experimental part of the study, the administration of doxorubicin in a cumulative dose of 15 mg/kg intraperitoneally to rats with non-alcoholic steatohepatitis leads to maximum changes in the small intestine homogenate, characterized by a 1.67-fold increase in the content of TBA reagents, a 3.62-fold decrease in catalase activity, a 1.45-fold decrease in citrulline content, and a 1.23-fold increase in N-acetylneuraminic acid level (p˂0.05) compared with the control. Histologically, the small intestinal mucosa showed a pronounced leukocyte infiltration of the villi lamina propria with macrophages, plasma cells, lymphocytes and neutrophilic granulocytes. The administration of S-ademethionine at a dose of 100 mg/kg on the background of doxorubicin infusion to rats with non-alcoholic steatohepatitis reduced the prooxidant-antioxidant imbalance, which prevented the development of cytostatic-induced mucositis. Histologically, we observed the restoration of the villous epithelium and the appearance of mitoses in exocrinocytes. In patients who had primary clinical signs of intestinal lesions in the form of diarrhea syndrome, the progression of B-cell chronic lymphocytic leukemia and B-cell non-Hodgkin's lymphoma from small lymphocytes was associated with the development of liver injury in 37, 14% (13/35) of patients, which was accompanied by a 1.25-fold increase in N-acetylneuraminic acid and a 1.2-fold decrease in citrulline (p˂0.05) in serum compared to normal levels on the background of oxidative stress activation. In these patients, chemotherapy was accompanied by an increase in the frequency of cholestatic-type biochemical liver tests (76.9% vs. 38.5%, X2 (1, N=26) = 3.9; p=0.047), progression of oxidative stress and disorders of the arginine/citrulline cycle and intestinal mucosal barrier resistance. The combined administration of S-ademethionine and Bifidobacterium infantis 35624 during chemotherapy in these patients reduced the risk of cytostatic-induced hepatotoxic reactions (15.4% vs. 76.9%, X2 (1, N=25) = 9.07; p=0.002) with the restoration of the functional state of the intestinal mucosa. In patients with multiple myeloma who had primary clinical signs of intestinal injury in the form of diarrheal syndrome, the progression of the disease was accompanied by the formation of liver damage in 86.8% (33/38) of patients, characterized by the development of cytolysis syndrome and accompanied by activation of oxidative stress and a decrease in the concentration of citrulline by 1.22 times (p˂0.05) in the blood serum compared with the normal. Under the influence of chemotherapy, 91.6% (11/12) of patients with multiple myeloma developed cholestatic-type biochemical liver tests, which was accompanied by a deepening of prooxidant-antioxidant imbalance and impaired intestinal function. The combined administration of L-ornithine-L-aspartate and Bifidobacterium infantis 35624 in the setting of chemotherapy in patients with multiple myeloma reduced the likelihood of cytostatic-induced hepatotoxic reactions (8.3% vs. 76.9%, X2 (1, N=25)=17.63; p=0.00002), reduced the activity of oxidative stress and restored the integrity and functional state of the intestine.