Features of Microcirculatory Disorders in Gastroesophageal Reflux Disease

The dissertation is devoted to the study of the features of microcirculation in the esophageal and gastric mucosa in patients with gastroesophageal reflux disease (GERD). The research is aimed at assessing the role of tissue blood flow disturbances in the pathogenesis of GERD and their relationship with the severity of mucosal damage. For the first time, laser Doppler flowmetry was applied to study microcirculation in the esophageal mucosa, which made it possible to identify microcirculatory disorders in various forms of the disease, including endoscopically negative GERD. A comparative evaluation of the effectiveness of antisecretory therapy (rabeprazole, omeprazole, famotidine) and its effect on the dynamics of microcirculatory parameters was carried out, which is important for individualizing treatment and improving the diagnosis of this disease.

Relevance of the problem.

The problem of gastroesophageal reflux disease (GERD) has recently attracted the attention of researchers and practicing physicians in many countries around the world. This is primarily due to the growing prevalence of GERD, the wide range of complaints presented by patients, including extra-esophageal manifestations, the development of such serious complications as Barrett's esophagus and esophageal adenocarcinoma, as well as the considerable duration of conservative therapy and, in a number of cases, the inevitability of surgical intervention [29, 30, 81]. It is rightfully considered a disease of the 21st century, since in recent years there has been a tendency toward a decrease in the incidence of gastric and duodenal ulcer disease and an increase in the incidence of GERD [30, 105]. Despite the close attention paid to this problem in recent years and the in-depth study of its etiology, pathogenesis and treatment, many questions remain unclear. The majority of researchers consider GERD to be a polyetiological disease and identify a number of factors in its development. By analogy with peptic ulcer disease, many authors examine the etiopathogenesis of GERD from the standpoint of evaluating a multilevel system of aggressive and protective factors. GERD is thought to develop as a result of an imbalance between the aggressive impact of the refluxed components and the three-stage defense system of the esophagus, which includes anti-reflux barriers, acid clearance mechanisms, and tissue resistance [81, 183, 226]. The components that determine the damaging properties of the refluxed substances are represented by hydrochloric acid, pepsin, bile acid salts (conjugated and free) and pancreatic enzymes (trypsin, lipases) [28, 29, 31, 32, 59, 88, 160]. Esophageal damage is determined by the pH value of the gastric contents. At neutral or alkaline pH, the damaging factors are free bile acid salts and pancreatic enzymes. However, the relationship between the rate of secretion of pepsin, bile salts and acid in the development of GERD has not been established. An important role in preventing damage to the esophageal mucosa is assigned to timely esophageal clearance [106]. The esophageal mucosa also possesses mechanisms capable of preventing its damage even after a reflux event has occurred. However, according to the modern classification, the presence of GERD does not imply obligatory instrumentally confirmed damage to the esophageal mucosa [202]. The presence of a certain amount of pepsin or bile acids in the esophageal lumen is necessary for the development of GERD, and the disruption of protective factors promotes the development of damage (erosions) of the esophageal mucosa during reflux episodes. The defense system of the esophageal mucosa consists of three elements:

• pre-epithelial defense (salivary glands, submucosal glands of the esophagus), including mucin, non-mucin proteins, bicarbonates, prostaglandins E2, epidermal growth factor;

• epithelial defense, ensuring normal regeneration of the esophageal mucosa;

• post-epithelial defense, ensuring adequate blood flow and normal tissue acid-base balance [81].

Many authors distinguish impaired mucosal resistance as one of the important factors in the development of GERD. Its element is post-epithelial defense, which provides adequate blood flow and normal tissue acid-base balance. These factors are important for the normal functioning of the esophagus, while the degree of esophageal mucosal damage depends on the degree of disruption of the protective factors. We have found no studies on microcirculation in the esophagus. Although recently an increasing number of works have appeared testifying to the great importance of microcirculatory disorders in the pathogenesis of chronic gastritis, peptic ulcer, and erosive lesions of the gastroduodenal zone [7, 20, 49, 57, 65, 66, 208]. Many authors acknowledge the role of microcirculatory disorders in the formation of disturbances of physiological regeneration, trophism and protection of the gastric mucosa [27, 43, 71, 119, 153, 168]. The question of the features of the functioning of the microcirculatory system in the esophagus and of its disorders in GERD remains open.

Microcirculation represents the smallest structural and functional unit of the circulatory system, where interaction occurs between the blood flow and the activity of tissues, ensuring the performance of various cellular functions [52]. The microcirculatory bed combines exchange microvessels (predominantly capillaries) lacking a smooth muscle component, as well as afferent resistive (arterioles, metarterioles, precapillaries, precapillary sphincters, small arteries) and efferent capacitive (small veins, postcapillary venules) muscle-containing vessels and shunts with a diameter of up to 200 μm. One of the early signs of microcirculatory bed dysfunction is local spasm of arteriolar vessels, stagnant phenomena in the venular link, and a decrease in blood flow intensity in the nutritive link of the capillary bed. With the development of a pathological process associated with a volumetric deficit of capillary blood flow, the fine mechanisms that regulate rhythmic changes in tissue hemodynamics suffer. Disorders of capillary blood flow, usually beginning with a decrease in its intensity, lead to the development of capillary stasis in the nutritive link of the microcirculatory bed and to the appearance of the phenomenon of arteriolo-venular shunting [35]. Despite the obvious role of impaired blood circulation in the pathogenesis of peptic ulcer disease, chronic gastritis and chronic gastric erosions, we have found no studies on GERD in the literature available to us, although the pathogenesis of GERD shares many common factors with chronic gastritis, gastric and duodenal ulcer disease.

Taking into account the current data on the significance of microcirculatory disorders in the pathogenesis of chronic gastritis, peptic ulcer disease and chronic gastric erosions, it may be assumed that the study of microcirculatory disorders is important for the development and course of GERD. The possibility of operative monitoring of the microcirculatory state directly in the esophageal mucosa and of evaluating the effectiveness of drugs with the help of LDF is extremely relevant given the informativeness of this method regarding microcirculatory disorders in GERD patients. Consequently, the study of this problem, as well as the development of management tactics for patients with varying severity of GERD, are topical, will allow individualizing patient treatment, improving their quality of life, and shortening the duration of therapy.

Aim of the study

The aim of the present study was to investigate the features of the microcirculatory state in the esophageal and gastric mucosa in patients with gastroesophageal reflux disease and to determine the role of microcirculatory disorders in the pathogenesis of GERD.

Objectives of the study

1. To investigate the features of microcirculation in the esophageal and gastric mucosa in patients with gastroesophageal reflux disease.

2. To evaluate the dynamics of microcirculatory disorders and the clinical effectiveness of treatment in patients with gastroesophageal reflux disease during monotherapy with antisecretory drugs.

3. To carry out a comparative evaluation of treatment regimens with antisecretory drugs in relation to the varying severity of microcirculatory disorders.

Scientific novelty

For the first time, microcirculation of the esophageal mucosa has been studied by laser Doppler flowmetry. For the first time, microcirculatory disorders of the gastric and esophageal mucosa in GERD have been identified. For the first time, a relationship has been shown between the character of microcirculatory disorders and the degree of esophageal mucosal damage. For the first time, it has been established that the greatest degree of microcirculatory disturbance is observed in the area of the floor of an esophageal erosion or ulcer. In addition, in patients with gastroesophageal reflux disease, a relationship has been revealed between the level of tissue perfusion in the esophageal and gastric mucosa and the severity of mucosal damage. For the first time, the effect of H2-blockers and proton pump inhibitors on microcirculation in the esophageal mucosa has been investigated.

Practical significance of the work

Our studies have shown that changes in tissue blood flow in patients with gastroesophageal reflux disease are detected in 98% of cases. The studied microcirculatory parameters can be used as additional criteria for diagnosis, assessment of process severity, and severity of the patient's condition. The influence of changes in tissue blood flow on the severity of esophageal damage in GERD has been studied.

The possibilities of laser Doppler flowmetry in the diagnosis of non-erosive gastroesophageal reflux disease, in particular endoscopically negative GERD, have been revealed. This will expand the diagnostic capabilities during endoscopic examination, which is especially important for the outpatient-polyclinic level.

The obtained data make it possible to propose laser Doppler flowmetry as a necessary method for confirming endoscopically negative gastroesophageal reflux disease.

For an adequate assessment of patient management tactics, the therapy prescribed to the patient can be individualized based on the severity of the revealed microcirculatory disorders, which is important both for patients with gastroesophageal reflux disease and for practicing physicians.

The use in GERD patients of drug regimens based on a new-generation proton pump inhibitor, rabeprazole (pariet), allows achieving a faster clinical remission, higher rates of erosion epithelization, and rapid normalization of blood flow in the esophageal and gastric mucosa. With the use of omeprazole, the restoration of microcirculatory parameters is achieved more slowly, as is the clinical-endoscopic remission. H2-blockers can be used only in cases of intolerance to PPIs, in patients insensitive to them, or in stage 0-1 GERD.

Ways of implementing the study results

The LDF method has been introduced into the practice of the Central Clinical Hospital No. I of OAO RZD. The developed GERD treatment regimens are recommended and used in the gastroenterological and therapeutic departments of the Central Clinical Hospital No. I of OAO RZD. The obtained results are used in the educational process of the Department of Propaedeutics of Internal Diseases and Gastroenterology of the Moscow State University of Medicine and Dentistry and are incorporated in lectures, seminars and practical classes with students and listeners of the certification courses of the Faculty of Postgraduate Education of the Moscow State University of Medicine and Dentistry.

Main provisions of the dissertation submitted for defense

1. Changes in tissue blood flow in patients with gastroesophageal reflux disease have been revealed in the middle and lower thirds of the esophagus and in the fundal part of the stomach.

2. In endoscopically negative gastroesophageal reflux disease, changes in microcirculatory parameters that significantly exceed the control values have been noted in 91.4% of patients.

3. In catarrhal esophagitis, the greatest deviations in microcirculatory parameters are noted in the lower third of the esophagus and are characterized by increased blood inflow and stasis in the venular link of the microcirculatory bed.

4. In erosive esophagitis, the greatest deviations in microcirculatory parameters are noted in the lower third of the esophagus and are characterized, on the contrary, by decreased inflow with simultaneous outflow obstruction in the collecting part of the microcirculatory bed. The maximum decrease in microcirculatory parameters is observed in the area of the floor of an erosion or ulcer. In the tissues surrounding the floor of an erosion or ulcer, an increase in blood flow has been recorded.

5. Microcirculatory disorders in the esophageal mucosa depend on the intensity of the pathological acidification factors. Thus, the maximum pH-metry values were recorded in 100% of cases in patients with grade III reflux esophagitis; simultaneously, these patients also exhibited the most pronounced microcirculatory disorders.

6. The administration of rabeprazole at a dose of 20 mg twice daily leads to normalization of microcirculatory parameters in 78% of patients, omeprazole 20 mg twice daily in 55%, and famotidine 20 mg twice daily in 24% of patients.