Barrett's esophagus - Causes

In recent years, the incidence of Barrett's esophagus has increased, due to both an increase in the number of patients and a wider use of esophagoscopy in the examination with targeted biopsies and histological examination of biopsy material. Male gender, long-term gastroesophageal reflux disease (GERD), large sizes of the hernia of the esophageal opening of the diaphragm are often considered as risk factors for the development of Barrett's esophagus, and are also often associated with a high degree of dysplasia. Barrett's esophagus may appear in patients aged 20 to 80 years, with the most frequent occurrence being between 47 and 66 years, and in those suffering from GERD - from one year to 26 years. It has also been noted that Barrett's esophagus occurs more often in men. According to some 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 increasing age of patients (more often after 40 years) and duration of GERD. According to other data, Barrett's esophagus occurs in only 1% of cases in patients suffering from GERD (with a male-to-female ratio of 2:1). Unfortunately, there is no accurate data on the frequency of Barrett's esophagus and the subsequent development of esophageal adenocarcinoma due to various reasons (esophagoscopy is not always performed, including biopsy of suspicious areas for pathological damage to the esophageal mucosa, in addition, GERD patients do not always consult a doctor, even those who are recommended dynamic observation, etc.)

Among the etiologic factors of Barrett's esophagus, a certain role is given to the deterioration of the quality of life, smoking abuse, frequent alcohol consumption (even moderate beer consumption), the effects of various drugs that damage the stratified squamous epithelium of the esophagus (in particular, during chemotherapy with cyclophosphamide, 5-fluorouracil), gastroesophageal reflux. No differences have been found in the effect of smoking and alcohol consumption on the development of Barrett's esophagus, as well as between patients with Barrett's esophagus and patients with GERD in the stage of reflux esophagitis. However, according to our observations, it is still advisable for patients with GERD to refrain from drinking alcoholic beverages, especially those with a strength below 20 degrees, which significantly and for a longer period of time increase acid formation in the stomach compared to stronger alcoholic beverages.

The question of the possible connection between an increased body mass index (BMI) or its absence in patients with GERD, including complicated by Barrett's esophagus, is periodically discussed. One point of view: an 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 size in patients with GERD affects the development of Barrett's esophagus. It is also argued that an increase in height in people is a risk factor for the development of Barrett's esophagus.

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

The appearance of metaplasia is a consequence of the constant impact of aggressive substances (hydrochloric acid, pepsin, bile acids and pancreatic enzymes) that damage mature cells of the esophageal epithelium with simultaneous stimulation of distorted differentiation of immature, proliferating cells. In essence, at a certain stage, intestinal metaplasia is apparently an adaptive reaction of the human body, promoting the formation of cylindrical epithelium, which has greater resistance to damage to the epithelium by aggressive factors. However, the pathogenetic mechanism causing the appearance of metaplasia in Barrett's esophagus is not completely clear.

The development of intestinal metaplasia is possible not only proximally, but also directly in the Z-line area, and such intestinal metaplasia, according to some researchers, should not be considered as precancer. It is necessary to remember that the development of esophageal cancer is possible without the appearance of Barrett's metaplasia.

Dysplasia is most often considered as the most well-known sign of previous neoplastic changes in the mucosa of Barrett's esophagus and even by some researchers - as a neoplastic lesion of the columnar epithelium limited by the basement membrane, and, accordingly, a factor preceding malignant transformation. Dysplasia and cancer development in patients with Barrett's esophagus are usually associated with intestinal metaplasia. However, the detection of dysplasia in Barrett's esophagus is explained, first of all, by the variability in the prevalence of dysplasia.

When examining patients with Barrett's esophagus, low-grade dysplasia is detected in 4.7% of cases, and high-grade dysplasia in 2.5%. Unfortunately, there is no reliable data on the survival rate of patients with Barrett's esophagus after treatment. It is known that dysplasia does not always transform into cancer and can even undergo "reverse" development, i.e. disappearance. The level (severity) of dysplasia can only be determined by histological examination of biopsy material. When assessing biopsy material, it is often difficult to distinguish between high-grade dysplasia and carcinoma in situ. The latter term is increasingly used in practice due to possible confusion with intramucosal carcinoma. Significant differences are known in the interpretation of dysplasia in Barrett's esophagus based on histological examination of biopsies. Therefore, it is advisable to evaluate biopsy materials independently by two different pathologists.

Esophageal damage increases in intensity and extent in the presence of refluxes containing acid, bile, and pancreatic enzymes. Under the influence of bile salts, cyclooxygenase-2 (COX-2) is activated, the suppression of which in laboratory rats leads to a decrease in the risk of cancer development. In patients with dysplasia and cancer, an increase in the level of COX-2 suppression has been established.

The development of GERD, including the appearance of Barrett's esophagus, is largely associated with an imbalance between the impact of various aggressive factors on the mucous membrane and the state of the protective factors of the mucous membrane. The protective factors include mechanical clearance (normal peristaltic activity and tone of the thoracic esophagus), normal chemical clearance (optimal production of saliva and bicarbonates, which have a neutralizing biological effect), resistance of the esophageal mucosa, normal motility of the esophagus, stomach and duodenum, as well as the "antireflux barrier" of the esophageal-gastric junction and the lower esophageal sphincter. Along with the lower esophageal sphincter, the angle of His and the crura of the esophageal opening of the diaphragm are directly involved in the formation of the "locking" barrier.

Acid reflux into 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 occurrence of DGE reflux is possible both in healthy people (a physiological act that occurs more often during the day, mainly after a large meal and "gas-forming" drinks, and less often at night), and in sick people for whom the reflux time, during which the pH level in the esophagus is less than 4, is more than 5% of the total time of intraesophageal pH-metry. It is generally accepted that in the lower third of the esophagus, the pH, according to intraesophageal pH-metry, is normally 6.0; the occurrence of acid reflux is possible at a pH of less than 4 or alkaline (bile) reflux - at a pH of more than 7.0.

Reflux of bile into the esophagus is increasingly considered as one of the significant factors underlying the failure of drug therapy for GERD complicated by Barrett's esophagus, based only on the use of proton pump inhibitors in the treatment of patients. According to our observations, long-term and continuous treatment of patients with proton pump inhibitors leads to a decrease in the secretion of acid by parietal cells of the gastric mucosa, which creates conditions for an increase in the concentration of bile acids (in the absence of significant dilution of bile acids secreted by parietal cells of the gastric mucosa with acid), which, in turn, creates conditions for increased pathological action of bile acids (salts) on the esophageal mucosa, leading to the appearance (progression) of Barrett's esophagus.

The intensity of pathological changes in the mucous membrane of the antrum of the stomach caused by bile in patients with Barrett's esophagus is more pronounced in chronic gastritis associated with the effect of bile on the mucous membrane than in patients with uncomplicated GERD and in patients with chronic gastritis and non-ulcer dyspepsia, which indicates the pathological role of bile contained in the refluxate as a possible factor in the development of intestinal metaplasia and malignancy of the esophagus.

An examination of pathophysiological abnormalities as measured by motility, pH, endoscopy, and Bilitec testing, as well as factors associated with Barrett's esophagus, showed that women with evidence of gastroesophageal reflux (compared to men) were significantly less likely to have a positive 24-hour pH test, a lower esophageal sphincter defect, or a hiatal hernia; women with gastroesophageal reflux had significantly lower esophageal acid exposure. Increased esophageal bilirubin exposure was the only significant factor associated with Barrett's esophagus in both men and women with GERD. Apparently, women and men with Barrett's esophagus have comparable severity of DGE reflux, and female gender does not protect against the development of Barrett's esophagus in patients with clinically evident GERD. Esophageal exposure of bilirubin in such patients is a leading factor in the development of Barrett's esophagus, especially with long-term treatment with acid-suppressive therapy.

These data to a certain extent confirmed our observations on the need to take into account the effect of bile acids on the esophageal mucosa when choosing a treatment option for patients with GERD, including those with Barrett's esophagus, and, if necessary, to use drugs that eliminate the pathological effect of bile acids in the treatment of patients (for example, additionally prescribe non-absorbable antacid drugs to patients). Another argument for this conclusion was the previously identified fact that the level of acid production in both patients with GERD and patients with Barrett's esophagus is not always elevated.

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Barrett's esophagus and helicobacter pylori

There are various data on the frequency of Helicobacter pylori (HP) in patients with Barrett's esophagus, apparently largely dependent on the methods for determining the prevalence of Barrett's esophagus and HP, the population, etc. In patients suffering from GERD, HP is observed in 44.2% of cases, while in Barrett's esophagus - in 39.2% of cases (statistically unreliable). When dividing patients with Barrett's esophagus into subgroups depending on the absence of dysplasia, the presence of low-grade dysplasia, high-grade dysplasia, or adenocarcinoma, it was found that the prevalence of HP was significantly lower in patients with high-grade Barrett's dysplasia (14.3%) and adenocarcinoma (15%) compared with patients in 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 with GERD, high-grade Barrett's dysplasia and esophageal adenocarcinoma are much more common in patients not infected with HP, which apparently plays a protective role, reducing the likelihood of adenocarcinoma development from the epithelium considered characteristic of Barrett's esophagus.

As early as 1998-2001, this hypothesis was proposed at the Central Research Institute of Gastroenterology (Moscow) (CRIG) based on an analysis of the results of studies that established the following fact: with a decrease in the frequency of HP colonization of the gastric mucosa in GERD, the likelihood of more pronounced pathological changes in the esophageal mucosa increases, i.e., a more severe course of GERD is noted. This position is supported by the fact that secondary hypersecretion of acid after treatment with omeprazole is observed in HP-negative individuals. The degree of this hypersecretion correlates with the level of increase in intragastric pH during treatment. In HP-positive individuals, this phenomenon is masked by persistent inhibition of hydrochloric acid secretion.

The Central Research Institute of Gastroenterology has established that HP eradication worsens the long-term treatment results of patients with GERD, which is largely due to an increase in the level of acid secretion, which is an aggressive factor. It is obvious that HP infection reduces the risk of esophageal cancer. Colonization by CaA-positive HP strains can play a protective role in relation to the formation of short and long segments of Barrett's esophagus, as well as to their malignant degeneration, regardless of the length of the esophageal segment.

What causes peptic ulcer of the esophagus? This issue has not been discussed much lately. Previously, researchers mentioned the occurrence of intestinal and gastric metaplasia, which occurs against the background of stratified squamous epithelium in the terminal section of the esophagus, while some believed that in areas of gastric metaplasia, peptic ulcer of the esophagus may form, and in areas of intestinal metaplasia, adenocarcinoma of the esophagus. Some Western researchers usually mention only intestinal metaplasia with the presence of specialized cylindrical (prismatic) epithelium as a risk factor for the occurrence of adenocarcinoma of the esophagus, bypassing the question of what epithelium actually causes ulcer of the esophagus.

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