Barrett's esophagus: causes

In recent years, the frequency of Barrett's esophagus has been increased, due both to the increase in the number of patients and to the wider use of esophagoscopy in the examination with targeted biopsies and histological examination of the biopsy material. Male sex, a long-term gastroesophageal reflux disease (GERD), large hernia of the esophageal opening of the diaphragm are often considered as risk factors for the development of the Barrett's esophagus, and are also often associated with a high degree of dysplasia. The appearance of Barrett's esophagus is possible in patients between the ages of 20 to 80 years, with most often between the ages of 47 and 66 years, in those suffering from GERD from one year to 26 years. It is also noted that Barrett's esophagus often occurs in men. According to one data, Barrett's esophagus develops in 20-80% of cases in patients with GERD with reflux-esophagitis due to prolonged acid reflux, and the likelihood of its occurrence increases with the age of the patients (more often after 40 years) and the duration of GERD. According to other data, Barrett's esophagus occurs only in 1% of cases in patients suffering from GERD (in the ratio of men and women 2: 1). Unfortunately, accurate data on the incidence of Barrett's esophagus and subsequent adenocarcinoma of the esophagus are not yet available due to various reasons (esophagoscopy is not always carried out, including biopsies of suspicious areas for pathological lesions of the esophagus mucosa, besides, not always patients with GERD address to the doctor, even those who are recommended for dynamic observation, etc.)

Among the etiological factors of the appearance of Barrett's esophagus, a certain role is played by the deterioration of the quality of life, the abuse of tobacco, the frequent use of alcohol (even moderate consumption of beer), the effects of various drugs damaging the multilayered squamous epithelium of the esophagus (in particular, with chemotherapy with cyclophosphamide, 5-fluorouracil) gastroesophageal reflux. There were no differences in the effect of smoking and alcohol use on the development of Barrett's esophagus, and between patients with Barrett's esophagus and GERD patients in the stage of reflux esophagitis. However, according to our observations, it is still advisable for patients with GERD to refrain from taking alcoholic beverages, especially a strength below 20 degrees, significantly and for a longer period of time increasing acidity in the stomach compared to stronger alcoholic beverages.

Periodically, the issue of a possible association of an increased body mass index (BMI) or its absence in patients with GERD, including that complicated by Barrett's esophagus, is discussed. One point of view: increased BMI does not affect the frequency of typical reflux symptoms, only in young people, an increase in BMI can be considered as a risk factor for the development of Barrett's esophagus; according to another opinion, an increase in waist circumference in GERD patients affects the development of Barrett's esophagus. It is also alleged that an increase in people's growth is a risk factor for Barrett's esophagus.

Metaplasia is the persistent transformation of one tissue into another, different from the first in its structure and function, while maintaining its basic species. Damage to the mucosa of the esophagus with DHE refluxes, primarily acid, bile acids and pancreatic enzymes, promotes the development of a "chemical" gastritis on the pathologically altered epithelium of the terminal esophagus, manifested by dystrophic and inflammatory changes in the mucous membrane, including the appearance of intestinal and / or gastric metaplasia. It is believed that patients with Barrett's esophagus have more prerequisites for the appearance of gastritis associated with bile exposure than patients with uncomplicated GERD or with non-ulcerative (functional) dyspepsia. The presence of "chemical" gastritis can contribute to the development of intestinal metaplasia and dysplasia of the epithelium of the mucosa of the esophagus.

The appearance of metaplasia is a consequence of the constant influence of aggressive substances (hydrochloric acid, pepsin, bile acids and pancreatic enzymes) damaging the mature cells of the esophagus epithelium with simultaneous stimulation of distorted differentiation of immature, proliferating cells. Essentially, at a certain stage, intestinal metaplasia appears to be an adaptive response of the human body, which contributes to the formation of a cylindrical epithelium, which has greater resistance to epithelial damage by aggressive factors. However, the pathogenetic mechanism that causes the appearance of metaplasia in the Barrett's esophagus is not completely clear.

The development of intestinal metaplasia is possible not only proximal, but also directly in the Z-line region, and such intestinal metaplasia, according to some researchers, should not be considered a precancerous. It should be remembered that the development of esophageal cancer is possible without the appearance of Barrett's metaplasia.

Dysplasia is most often seen as the most well-known symptom of previous tumoral changes in the mucosa of Barrett's esophagus and even by some researchers - as a neoplastic lesion of the cylindrical epithelium confined to the basal membrane and, accordingly, the factor preceding malignant transformation. Dysplasia and development of cancer in patients with Barrett's esophagus is usually associated with intestinal metaplasia. However, the detection of dysplasia in the Barrett's esophagus is explained, first of all, by the variability of the prevalence of dysplasia.

When examining patients with Barrett's esophagus, low-grade dysplasia is detected in 4.7% of cases, and a highly differentiated dysplasia is found in 2.5%. Unfortunately, there is no reliable information about the survival of patients with Barrett's esophagus after the treatment. It is known that dysplasia does not always transform into cancer and can even be subjected to "reverse" development, i.e., disappearance. The level (severity) of dysplasia can be determined only by histological examination of the biopsy material. When evaluating a biopsy material, it is often difficult to distinguish between high levels of dysplasia and carcinoma in situ. The latter term is increasingly used in practical work in connection with the possible confusion with intramucosal carcinoma. There are significant differences in the treatment of dysplasia in the Barrett's esophagus based on the histological examination of biopsies. Therefore, evaluation of biopsy materials is advisable to conduct two different pathomorphologists independently of each other.

Damage to the esophagus increases in its intensity and extent in the presence of reflux, containing in its composition, acid, bile, pancreatic enzymes. Under the influence of bile salts, cyclooxygenase-2 (COX-2) is activated, the suppression of its activity in laboratory rats leads to a reduction in the incidence of cancer risk. In patients with dysplasia and cancer, an increase in the level of suppression of COX-2 has been established.

The development of GERD, including the appearance of the Barrett's esophagus, is largely due to the imbalance between the effect on the mucous membrane of various aggression factors and the state of mucosal protection factors. The factors of protection include mechanical clearance (normal peristaltic activity and tone of the thoracic esophagus), normal chemical clearance (optimal saliva and bicarbonate production, neutralizing biological effect), resistance of the esophagus mucosa, normal state of esophagus, stomach and duodenal motility, and also "Antireflux barrier" of the esophageal-gastric junction and lower esophageal sphincter. Along with the lower sphincter of the esophagus, the angle of the jaw and the legs of the esophageal opening of the diaphragm are directly involved in the formation of the "blocking" barrier.

Reflux acid in the esophagus is usually considered as the main factor, which under certain conditions can be the most aggressive, causing damage primarily to the epithelium of the mucous membrane of the terminal section of the esophagus. In principle, the appearance of DHE reflux is possible both in healthy people (a physiological act that occurs more often in the daytime, mainly after a plentiful meal and "gas-forming" drinks, and less often at night), and in sick people who have reflux time during which in the esophagus, the pH level is less than 4, is more than 5% of the total time spent in the intra-esophageal pH-metry. It is generally believed that in the lower third of the esophagus the pH is normally 6.0, according to the intrasophageal pH-metry data; the appearance of acid reflux is possible at pH less than 4 or alkaline (bile) reflux - at pH more than 7.0.

Reflux of bile in the esophagus is increasingly considered as one of the essential factors underlying the failure of drug therapy for GERD, complicated by the Barrett's esophagus, based only on the use in the treatment of patients with proton pump inhibitors. According to our observations, prolonged and continuous treatment of patients with proton pump inhibitors leads to a decrease in acid secretion by parietal cells of the gastric mucosa, which creates conditions for increasing the concentration of bile acids (in the absence of significant dilution of bile acids released by parietal cells of the gastric mucosa), which, in in turn, creates the conditions for strengthening the pathological action of bile acids (salts) on the mucosa of the esophagus, leading to the appearance (progressively aniyu) Barrett's esophagus.

The intensity of pathological changes in the gastric mucosa of the antral stomach caused by bile in patients with Barrett's esophagus is more pronounced in chronic gastritis associated with the exposure of bile to the mucous membrane than in patients with uncomplicated GERD and in patients with chronic gastritis and nonulcer dyspepsia, which indicates a pathological the role of bile contained in refluxate, as a possible factor in the development of intestinal metaplasia and malignancy of the esophagus.

The study of pathophysiologic disorders based on motor, pH, endoscopic and Bilitec test results, as well as factors related to Barrett's esophagus, showed that for women with signs of gastroesophageal reflux (compared to men), a positive 24- hour pH test, defect of the lower esophageal sphincter or hernia of the esophageal opening of the diaphragm; in women with gastroesophageal reflux, a significantly lower exposure of acid in the esophagus was found. Increased exposure to the esophagus of bilirubin is the only reliable factor associated with Barrett's esophagus in both men and women with GERD. Obviously, women and men with Barrett's esophagus have a comparable burden of DHE reflux, and the female sex does not protect against the development of Barrett's esophagus in patients with clinically expressed GERD. Esophageal exposure of bilirubin in such patients is a leading factor in the development of Barrett's esophagus, especially with prolonged treatment with acid-suppressive therapy.

These data to some extent confirmed our observations on the need to take into account the influence of bile acids on the mucosa of the esophagus when choosing the treatment option for GERD patients, including the Barrett esophagus, and also, if necessary, to use drugs that eliminate the pathological effect of bile acids (eg , additionally appoint patients with nonabsorbable antacid preparations). Another argument of this conclusion was the previously revealed fact - the level of acid production in both patients with GERD and in patients with Barrett's esophagus is not always increased.

[1], [2], [3]

Esophagus of barrett and helicobacter pylori

Various information is known about the frequency of Helicobacter pylori (HP) in patients with Barrett's esophagus, apparently largely dependent on the methods of ascertaining the prevalence of the Barrett's esophagus and HP, the population, etc. In patients suffering from GERD, HP is reported in 44, 2% of cases, while in Barrett's esophagus - in 39.2% of cases (statistically unreliable). In the distribution of patients with the Barrett esophagus into subgroups, depending on the absence of dysplasia, the presence of low-grade dysplasia, high grade, or adenocarcinoma, it is established that the prevalence of HP is significantly lower in patients with high-grade Barrett dysplasia (14.3%) and adenocarcinoma (15%) in compared with patients of the control group (44.2%), patients with Barrett's esophagus (35.1%) or Barrett's esophagus with low grade dysplasia (36.2%, p = 0.016). Among patients suffering from GERD, high-grade Barrett dysplasia and esophagus adenocarcinoma are more common in patients not infected with HP, which appears to play a protective role, reducing the likelihood of developing adenocarcinoma from the epithelium deemed to be characteristic of Barrett's esophagus.

Back in 1998-2001. This hypothesis was proposed at the Central Scientific Research Institute of Gastroenterology (Moscow) (CNIIG) on the basis of an analysis of the results of the studies, according to which the following fact was established: with a decrease in the frequency of dissemination of HP of the gastric mucosa in GERD, the probability of more pronounced pathological changes in the mucosa esophagus, i.e., a heavier GERD is observed. In favor of this provision is evidence that secondary hypersecretion of acid after treatment with omeprazole is noted in HP negative individuals. The degree of this hypersecretion is correlated with the level of intragastric pH increase during treatment. In HP-positive individuals, this phenomenon is masked by persistent inhibition of hydrochloric acid secretion.

It has been established in the CNIIG that eradication of HP worsens the long-term results of treatment of patients with GERD, which is largely due to an increase in the level of acid secretion, which is an aggressive factor. Obviously, HP infection reduces the risk of esophageal cancer. The actual colonization with CaA-positive HP strains may play a protective role in relation to the formation of short and long segments of the Barrett's esophagus, as well as to their malignant degeneration, regardless of the extent of the esophagus segment.

What causes peptic ulcer of the esophagus? This issue has not been discussed lately. Previously, researchers mentioned the appearance of intestinal and gastric metaplasia, which occurs against the background of multilayered flat epithelium in the terminal section of the esophagus, while some believed that the formation of peptic ulcer of the esophagus in the areas of gastric metaplasia, and esophageal adenocarcinoma in the areas of intestinal metaplasia. Some Western researchers usually refer only to intestinal metaplasia with the presence of specialized cylindrical (prismatic) epithelium as a risk factor for the appearance of adenocarcinoma of the esophagus, bypassing the question of which epithelium itself causes the ulcer of the esophagus.

[4], [5], [6], [7], [8], [9], [10], [11], [12]