An experimental model of non-alcoholic steatohepatitis (NASH) and hypercholesterolemia was developed for the first time, which reduced the duration of the pathological condition modeling by 28-30 days and proved to be simpler in performance. According to the developed scheme NASH with HC was formed on the 90th day. The biochemical study of the blood serum showed a significant hypolipidemic effect in all indices of the lipidogram (p<0.04) and a marked decrease in the activity of liver enzymes (p<0.02) on the 45th day of experimental lipid-lowering therapy with rosuvastatin, ezetimibe and complex hepatoprotector; there was improvement of microstructure: absence of cells inflammation, bridge-like fibroids, fatty hepatosis of 0-I degree in the liver tissue.
The results of molecular genetic study confirmed the expediency of identifying a biomarker that was associated with a change of pharmacological response of HMG-CoA reductase inhibitors. Conducted pharmacogenetic testing of rs4149056 polymorphism (Val1174/Ala, c.521T > C) of the SLCO1B1 gene found that of 73 patients with familial hypercholesterolemia (FHC) and NASH, 42 (57.5%) patients had wild-type carriers (Val/Val, c.521TT), 26 patients (36%) - heterozygous carrier (Val/Ala, c.521TC) and 7 patients (6.5%) - homozygous carrier (Ala/Ala, c.521CC); then all patients received a statin according to the dosing algorithm.
The evaluation of clinical efficacy of the developed pathogenetically reasonable hypolipidemic therapy was made. Additionally to rosuvastatin and ezetimibe, administration of a complex hepatoprotector given to the patients with FHC and NASH for 90 days, had led to a significant regression of LDL levels by 52% (p=0.001) and increase in HDL by 78% (p=0.001) compared to a baseline. The activity of liver enzymes was lower compared to a baseline: ALT by 55% (p=0.001), ACT by 66% (p=0.001), the concentration of IL-6 decreased by 41% (p=0.001), the concentration of CK-18 fragments was lower by 53% (p=0.001). CK-18 has a statistically significant, direct, close correlation with the data on the activity of hepatic transaminases (with ALT r=0.76, p=0.01; ACT r=0.77, p=0.01), LDL levels (r=0.81, p=0.01), liver ultrasound results (r=0.59, p=0.01). The correlation analysis of the concentration of IL-6 revealed a reliable, positive, close correlation with liver enzymes (ALT r=0.95, p=0.01; AST r=0.97, p=0.01), LDL level (r=0.96, p=0.01).
The prognosis of application of the developed drug therapy in patients with FHC and NASH, by constructing the function of the Gompertz S-curve demonstrated that the proposed complex therapy allowed achieving a level of LDL 2.5 mmol/l for 3 months, and the concentration of CK-18 fragments was 98.02 IU/l for 6 months from the beginning of the treatment.
A questionnaire was first developed and applied to subjective, screening assessment of a quality of life in the patients with FHC and NASH (Modified Questionary Quality of Life in Patients with Familial Hypercholesterolemia and Nonalcoholic Steatohepatitis). The conducted statistical analysis revealed a significant close correlation between MQLFS and standard questionnaires, laboratory and instrumental examination results, good and excellent quality of indices - AUC area was 0.63-1.0 (p<0.04).
