Bobronnikova L. Pathogenetic mechanisms of the associated clinical course of chronic cholecystits and primary hypertenision and therapeutic approaches.

Українська версія

Thesis for the degree of Doctor of Science (DSc)

State registration number

0510U000096

Applicant for

Specialization

  • 14.01.02 - Внутрішні хвороби

06-11-2009

Specialized Academic Board

Д 64.600.04

Essay

Object of the study: chronic cholecystitis (CC), primary hyprtension (PH) and their combination. Purpose of the research : to work out a pathogenetically grounded clinical monitoring system with the establishment of indicators of functional-metabolic disturbances and assessment of treatment efficacy in patients with a combined course of CC and PH. Methods of the research: clinical-anamnestic, biochemical, immunological, functional, morphological and clinical-analytical ones, as well as clinical-informative method, statistical method. Theoretical and practical results: the practical value of the research consists in the realization of the systems approach to the improvement of diagnosing and treating patients with combined clinical variants (CCV) on the basis of revealing integrative synergic changes of the morphofunctional state of the gallbladder (GB) and myocardium, as well as functional-metabolic disturbances. Practically significant is a developed clinical-functional diagnosis systemization on the cellular, organic, systemic and intersystemic levels, which makes it possible to increase the informative value of the GB state diagnosis from pathogenetically grounded positions by the indices of microelement homeostasis and GB kinetics type. The revealed relationships between the state of the central haemodynamics, bile extraction kinetics and metabolic provision for oxidative homeostasis serve as the ground for spreading the basic therapy of patients with a combined course of CC and PH, thereby excluding polypragmasy and ensuring pathogenetic correction on the level of both the hepatobiliary (a correction of the GB kinetics disorders) and cardiovascular ( a correction of the state of the vascular smooth-muscle coat) systems due to the pharmacotherapeutic synergism of the drugs chosen. The consideration of combined factors of atherogenesis (a higher level of total cholesterin in blood serum owing to low-density lipoproteins) and lithogenesis (disturbances in the physical and biochemical properties of bile) and their corresponding markers in the clinical monitoring system make sit possible to prevent a mutually aggravating course of the diseases. A differentiated use of calcium antagonists, angiotensin-converting enzyme inhibitors, antioxidant and microelement homeostasis-correcting drugs was grounded in a system of combined treatment of patients ill with CC together with PH. Informative indices were established for assessing the character of haemodynamic changes and functional state of the myocardium in patients with a combined course of CC and PH. Peculiarities of disturbances in haemodynamics and remodelling of the myocardium were clarified, therewith necessitating their use in clinical monitoring. An algorithm of the morphofunctional state of GB with regard for inflammation indicators of its mucous membrane (MM) was worked out, thereby making it possible to improve the diagnosis of CC combined with PH. Novelty: for the first time, on the basis of an in-depth study of destabilization factors of the morphofunctional continuum of the cardiovascular and hepatobiliary systems, a theoretical generalization and a new solution were given for such a scientific problem as the development of a pathogenetically grounded system of clinical monitoring with regard for the leading risk factors, common for CC and PH, establishment of indicators of functional-metabolic disturbances, a microelement imbalance and their influence on the development of the combined pathology, thereby making it possible to substantiate principles of the differentiated treatment of such patients. A causal relationship was proved between the metabolic provision of oxidative homeostasis and haemodynamic disturbances, as well as changes in the functional state of the myocardium in CC combined with PH. It was established that the presence of common pathogenetic relationships between the central haemodynamics state and bile excretion kinetics, which were realized on the level of the muscular coat of GB, vascular smooth muscles and through the left ventricle remodelling, caused peculiarities in the clinical course of PH combined with CC, myocardial contractility with a decrease of its inotropic function in particular, and necessitated a differential pharmacotherapeutic correction. It was found out that the morphofunctional state of the bile excretion system, kinetic disorders of bile excretion in particular, was a significant factor, capable of influencing the course of PH through metabolically grounded disturbances in the concentration and excretion functions of GB as a result of an imbalance of the amino acid and microelement blood serum composition. For the first time, a distribution of structural elements in the GB wall, which contain NADPH diaphorase, as a marker of the inducible form of NO synthase ( iNOS), was characterized and the role of iNOS expression with NADPH diaphorase activity of epitheliocytes and stromal elements of GB MM in the realization of the pathomorphosis of CC combined with PH was proved. From the positions of a system analysis of the universal mechanism of reaction of the immune system, its general and specific responses on the level of interleukins were revealed. It was proved that a progress of structural disorganization processes in GB MM of patients with CCV of CC and PH was accompanied with an activation of the cytokine link of regulation, thereby inducing iNOS expression. Dynamic changes in the cytokine system depended upon the time factor and were characterized by a gradual depletion of the immune system and a quantitative decrease of cardiomyocytes, which produced cytokines. It was established that a disorder in the bile excretion kinetics occurred against a background of a metabolic lesion of the epithelium, vascular smooth-muscle tissue and muscular coat of GB, endothelium and nervous tissue, which was mediated by iNOC expression as a result of GB infection with toxicogenic strains of Helicobacter pylori CagA+ , VacA+ and a stimulatory effect of cytokines. A concept of the integrative character of oxidative homeostasis reactions in pathogenetic mechanisms of combined pathology was further developed and clinically concretized. General regularities in lesions of cell membranes manifested themselves at the level of GB and cardiovascular system, with a resultant formation of metabolic preconditions for a combined course of PH and CC, facilitated by an intensive accumulation of secondary decomposition products of lipid oxidation in blood and an activation of the mast-cell component in GB MM. It was proved that any individual medical tactics, the choice of remedies and the efficacy of therapy depended upon the functional polymorphism of CCV with the corresponding state of functional-metabolic disturbances, the latter being caused by a type of GB dyskinesia, haemodynamic disorders and processes of the myocardium remodelling. A differential use of medical remedies with an antioxidant effect and drugs, which influenced the ratio of bioelements on the level of membranes and cell bioenergetics was substantiated in a system of integrated treatment of patients with CC combined with PH. Degree of introduction: results of the researches were introduced into the work of regional hospitals of the Kharkiv, Dniepropetrovsk, Plotava Regions, Kharkiv City Hospital No. 18, Merefa, Chuguev, Balakleya, Pervomaysk, Dergachi Central District Hospitals of the Kharkiv Region. Results of the studies of the clinical course of PH and CC, diagnosis and principles of a differentiated correction were introduced into the process of training at therapeutic departments of Kharkiv National Medical University. Sphere of application: medicine, internal medicine.

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