Gastroesophageal reflux disease (GERD) - Pathogenesis

In healthy individuals, gastroesophageal reflux may occur mainly during the daytime after meals (postprandial), between meals (interprandial) and much less frequently at night (in a horizontal position), but in these cases, intraesophageal pH decreases to less than 4.0 for no more than 5% of the total time of esophageal pH monitoring.

The results of intraesophageal pH monitoring during the day in healthy volunteers showed that there are no more than 50 episodes of gastroesophageal reflux with a total duration of no more than 1 hour. Under normal conditions, the pH in the lower third of the esophagus is 6.0. During gastroesophageal reflux, the pH either decreases to 4.0 - when acidic stomach contents enter the esophagus, or increases to 7.0 - when duodenal contents mixed with bile and pancreatic juice enter the esophagus.

Normally, the following protective mechanisms are activated to prevent damage to the mucous membrane (MM) of the esophagus:

1. Antireflux barrier function of the gastroesophageal junction and lower esophageal sphincter.
2. Esophageal cleansing (clearance).
3. Esophageal mucosal resistance.
4. Timely removal of gastric contents.
5. Control of the acid-forming function of the stomach.

Disturbances in the coordination of the first three mechanisms are of greatest importance in the development of reflux disease.

The most common reasons for a decrease in the function of the antireflux barrier are the following:

1. Hernias of the esophageal opening of the diaphragm (more than 94% of patients with reflux esophagitis have a hiatal hernia).
2. Increased frequency of spontaneous relaxations.
3. Decreased pressure in the lower esophageal sphincter.

The action of the antireflux mechanism is ensured by the following factors:

• the length of the abdominal part of the esophagus;
• angle of His (the acute angle where the esophagus enters the stomach; normally, its dimensions range from 20 to 90 degrees, depending on the person’s constitution);
• legs of the diaphragm;
• Gubarev's fold, formed by the mucous rosette of the cardia.

The Morozov-Savvin ligament (phrenic-esophageal ligament) plays an important role in fixing the esophagus in the esophageal opening of the diaphragm. It resists the upward traction of the cardiac section, allowing movements in the esophagus during swallowing, coughing, and vomiting. The peritoneum also contributes to fixation of the esophagus: on the right, the abdominal section of the esophagus is held by two peritoneal sheets that form the hepatogastric ligament, and behind - by the gastropancreatic fold of the peritoneum. The periegastric fatty tissue, the gas bubble of the stomach, and the left lobe of the liver also contribute to fixation of the esophagus. Atrophy of muscle fibers in the area of the esophageal opening of the diaphragm, and, above all, the Morozov-Savvin ligament, which occurs with age or for other reasons, leads to expansion of the esophageal opening of the diaphragm, the formation of a “hernial orifice”, increased mobility of the esophagus and predisposes to the development of a hernia of the esophageal opening of the diaphragm.

A hernia of the esophageal opening of the diaphragm (HED) is a chronic recurrent disease associated with the displacement of the abdominal esophagus, cardia, upper stomach, and sometimes intestinal loops through the esophageal opening of the diaphragm into the chest cavity (posterior mediastinum). The first descriptions of HED belong to the French surgeon Pare Ambroise (1579) and the Italian anatomist G. Morgagni (1769). The frequency of detection of HED varies from 3% to 33%, and in the elderly up to 50%. Hernias of the esophageal opening of the diaphragm account for 98% of all diaphragmatic hernias. It is important to note that in 50% of patients it does not cause any clinical manifestations and, therefore, is not diagnosed.

There are congenital hernias, the formation of which is associated with uneven development of the muscles and openings of the diaphragm, incomplete descent of the stomach into the abdominal cavity, obliteration of the air-intestinal pockets, weakness of the connective tissue in the esophageal and aortic openings of the diaphragm. Most GERD in adults are acquired and are formed as a result of the combined effect of various factors, of which the main role is given to the weakness of the connective tissue structures and atrophy of the muscle fibers that form the esophageal opening of the diaphragm, increased intra-abdominal pressure and upward traction of the esophagus in dyskinesia of the digestive tract and diseases of the esophagus.

According to H. Bellmann et al. (1972), GERD is a common symptom of generalized weakness of connective tissue (minor collagenosis). It is assumed that the pathogenesis is due to insufficient absorption of ascorbic acid and impaired collagen synthesis. Observations indicating frequent combinations of GERD with hernias of other localizations: inguinal, umbilical, linea alba, varicose veins of the lower extremities, diverticulosis of the gastrointestinal tract, confirm this hypothesis.

Increased intra-abdominal pressure is observed with pronounced flatulence, persistent constipation, pregnancy, especially repeated, uncontrollable vomiting, severe and persistent cough (it is known that 50% of patients with chronic obstructive bronchitis with a long history of the disease have GERD), ascites, in the presence of large tumors in the abdominal cavity, and severe obesity. Hernias often form after heavy physical exertion, especially in untrained individuals. This mechanism of hernia development is observed in young people. Some authors also attach importance to injuries, abdominal operations, in particular gastric resection, in the pathogenesis of hernia formation.

Functional disorders (dyskinesia) of the esophagus often occur in gastric ulcer and duodenal ulcer, chronic cholecystitis, chronic pancreatitis and other diseases of the digestive system. In hypermotor dyskinesia of the esophagus, its longitudinal contractions cause the esophagus to be pulled upward and contribute to the development of GERD. The Kasten triad (GERD, chronic cholecystitis, duodenal ulcer) and the Saint triad (GERD, chronic cholecystitis, colon diverticulosis) are known. A.L. Grebenev found chronic cholecystitis and cholelithiasis among patients with GERD in 12% of cases, and duodenal ulcer - in 23%.

There is no single classification of GERD. According to the classification based on the anatomical features of GERD, a sliding (axial) hernia is distinguished, characterized by the fact that the abdominal part of the esophagus, cardia and fundic part of the stomach can freely penetrate into the chest cavity through the expanded esophageal opening of the diaphragm and return back to the abdominal cavity. And also paraesophageal, in which the terminal part of the esophagus and cardia remain under the diaphragm, and part of the fundic part of the stomach penetrates into the chest cavity and is located next to the thoracic part of the esophagus. In the mixed variant of GERD, a combination of axial and paraesophageal hernias is observed.

Based on radiological findings, depending on the size of the prolapse (eventration) of the stomach into the chest cavity, I.L. Tager and A.A. Lipko (1965) distinguish three degrees of GERD.

In grade I GERD, the abdominal esophagus is located in the chest cavity above the diaphragm, the cardia is located at the level of the diaphragm, and the stomach is raised under the diaphragm. Excessive displacement of the abdominal segment is considered an initial hernia (vertical displacement normally does not exceed 3-4 cm). In grade II GERD, the vestibule and cardia lie under the diaphragm, and folds of the gastric mucosa are visible in the diaphragmatic opening. In grade III GERD, part of the stomach (body, antrum) falls into the chest cavity along with the abdominal segment of the esophagus and cardia.

According to clinical classifications of GERD (V.Kh. Vasilenko and A.L. Grebenev, 1978, B.V. Petrovsky and N.N. Kanshin, 1962), fixed and non-fixed hernias are distinguished. According to N.N. Kanshin, fixation of a hernia in the mediastinum is caused not by an adhesive process, but by negative intrathoracic pressure. Fixation and size of GERD are inversely related - the smaller the hernia, the greater its mobility and tendency to grow, and vice versa, the larger the hernia, the more often it is fixed and stable in size. Hernias are subdivided depending on the organs included in the hernial sac (esophageal, cardiac, fundal, antral, subtotal and total gastric, intestinal, omental), a congenital short esophagus (thoracic stomach) is distinguished. In addition, there is a classification of hernias depending on the complications that arise as a result of the presence of a hernia, the first of which is reflux esophagitis. A vicious circle occurs when GERD leads to reflux esophagitis, and the latter contributes to an increase in the hernia, due to the traction mechanism, as well as shortening of the esophagus as a result of the cicatricial inflammatory process.

The main role in the mechanism of cardia closure is given to the lower esophageal sphincter (LES). The LES is a smooth muscle thickening located at the junction of the esophagus and the cardiac section of the stomach, 3-4 cm long, with specific autonomous motor activity, its own innervation, and blood supply. These features allow us to distinguish the lower esophageal sphincter as a separate morphofunctional formation. Relaxation of the lower esophageal sphincter is stimulated by the vagus nerve through preganglionic cholinergic fibers and postganglionic noncholinergic and nonadrenergic nerve fibers. Sympathetic impulses increase the tone of the lower esophageal sphincter. In addition, the myogenic properties of the smooth muscles of the lower esophageal sphincter are affected by various humoral factors: gastrin, motilin, histamine, bombesin, vasopressin, prostaglandin F _2a, alpha-adrenergic agonists, beta-adrenergic blockers - increase the tone of the lower esophageal sphincter, and secretin, glucagon, cholecystokinin, neurotensin, gastric inhibitory polypeptide, progesterone, prostaglandin, alpha-adrenergic blockers, beta-adrenergic agonists, dopamine - decrease the tone of the lower esophageal sphincter. At rest, the muscle fibers of the esophagus are in a state of tonic constriction, therefore, under resting conditions in a healthy person, the esophagus is closed, while a pressure of 10 to 30 mm Hg is created in the lower esophageal sphincter. (depending on the breathing phase). The minimum pressure of the lower esophageal sphincter is determined after eating, the maximum at night. During swallowing movements, the tone of the muscles of the lower esophageal sphincter decreases and after the passage of food into the stomach, the lumen of the lower part of the esophagus closes. With GERD, there is hypotension or even atony of the lower esophageal sphincter, the pressure in the lower esophageal sphincter rarely reaches 10 mm Hg.

The pathophysiological mechanisms of spontaneous (or transient) relaxation of the lower esophageal sphincter are not yet fully understood. It may be due to a disturbance of the cholinergic effect or to an increase in the inhibitory effect of nitric oxide. Normally, relaxation of the lower esophageal sphincter lasts 5-30 sec. Most patients with GERD experience repeated episodes of spontaneous relaxation of the lower esophageal sphincter that cannot be adequately controlled. Transient relaxations of the lower esophageal sphincter may be a response to incomplete swallowing, bloating, so reflux episodes often occur after meals.

Relaxations of the lower esophageal sphincter may be associated with swallowing, which is observed in 5-10% of reflux episodes, the cause of which is impaired esophageal peristalsis. It should be noted that modern prokinetics are not effective enough in reducing the number of episodes of relaxation of the lower esophageal sphincter. In the future, it is still necessary to decipher the mechanisms of regulation of the function of the lower esophageal sphincter and introduce new prokinetic drugs into clinical practice.

Causes leading to increased frequency of episodes of spontaneous relaxation (relaxation) of the lower esophageal sphincter:

• disturbance of esophageal peristalsis (esophageal dyskinesia), leading to smoothing of the esophagogastric angle, reduction of pressure on the lower part of the esophagus in the chest. This is often facilitated by the patient's neurotic state or diseases such as systemic scleroderma, diaphragmatic hernia;
• hasty, fast and abundant eating, during which a large amount of air is swallowed, which leads to an increase in intragastric pressure, relaxation of the lower esophageal sphincter (overcoming its resistance) and the reflux of stomach contents into the esophagus;
• Veterism;
• peptic ulcer disease (especially with ulcer localization in the duodenum), with gastroesophageal reflux observed in 1/2 of patients;
• duodenostasis of any etiology;
• excessive consumption of fatty meat, refractory fats (lard), flour products (pasta, vermicelli, pastries, bread), hot spices, fried foods (these types of food contribute to prolonged retention of food in the stomach and increased intra-abdominal pressure).

The above factors cause the reflux of gastric or duodenal refluxate containing aggressive factors - hydrochloric acid, pepsin, bile acids, which causes damage to the mucous membrane of the esophagus. Such damage develops with sufficiently long contact of refluxate (more than 1 hour per day) with the mucous membrane of the esophagus, as well as with insufficient functioning of the protective mechanisms.

The second factor in the pathogenesis of GERD is a decrease in the clearance of the esophagus, consisting of a chemical one - a decrease in the content of hydrocarbonates in saliva and a decrease in the production of saliva as such, and a volumetric one - inhibition of secondary peristalsis and a decrease in the tone of the wall of the thoracic esophagus.

The esophagus is continuously cleared by swallowing saliva, eating and drinking, secretions of the glands of the submucosa of the esophagus and gravity. In GERD, there is a long contact (exposure) of aggressive factors of the gastric contents with the mucous membrane of the esophagus, a decrease in the activity of esophageal clearance and an increase in its time (normally it is on average 400 sec, with gastroesophageal reflux disease 600-800 sec, i.e. it is almost twice as long). This occurs as a result of esophageal dysmotility (esophageal dyskinesia, systemic scleroderma and other diseases) and dysfunction of the salivary glands (the amount and composition of saliva in healthy people is regulated by the esophagosalivary reflex, which is impaired in the elderly and with esophagitis). Insufficient salivation is possible with organic and functional diseases of the central nervous system, endocrine diseases (diabetes mellitus, toxic goiter, hypothyroidism), scleroderma, Sjogren's syndrome, diseases of the salivary glands, during radiation therapy of tumors in the head and neck area, and during treatment with anticholinergics.

The resistance of the esophageal mucosa is determined by a defense system consisting of three main parts:

• preepithelial protection (salivary glands, glands of the submucosa of the esophagus), including mucin, non-mucin proteins, bicarbonates, prostaglandin E2 _, epidermal growth factor;
• epithelial protection - normal regeneration of the esophageal mucosa, which can be divided into structural (cell membranes, intercellular junctional complexes) and functional (epithelial transport of Na ⁺ /H ⁺, Na ⁺ -dependent transport of CI- /HCO3; intracellular and extracellular buffer systems; cell proliferation and differentiation);
• post-epithelial protection (normal blood flow and normal tissue acid-base balance).

Based on the above, it can be stated that GERD occurs when there is an imbalance between the aggressive factors of the gastric contents and the protective factors with a clear predominance of aggressive factors.

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