Gastroesophageal reflux disease (GERD): pathogenesis

In healthy people, gastroesophageal reflux can occur mainly during the daytime after meals (postprandial), between meals (interprandially) and much less at night (in horizontal position), but in these cases the intra-esophageal pH drops to less than 4.0 for no more than 5% of the total time of pH monitoring of the esophagus.

The results of intrapischlear pH monitoring for 24 hours in healthy volunteers showed that the episodes of gastroesophageal refluxes are no more than 50 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 the acid content of the stomach gets into the esophagus, or rises to 7.0 - when the duodenal contents enter the esophagus with an admixture of bile and pancreatic juice.

In order to prevent damage to the mucous membrane (CO) of the esophagus, the following protective mechanisms are included:

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

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

Most often, the following causes lead to a decrease in the function of the antireflux barrier:

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

The effect of the antireflux mechanism is provided by the following factors:

• the length of the abdominal part of the esophagus;
• angle of the Hyis (acute angle of the esophagus into the stomach, in norm its sizes fluctuate from 20 to 90 degrees depending on the constitution of the person);
• the feet of the diaphragm;
• fold Gubarev, formed by a mucous rosette of cardia.

An important place in the fixation of the esophagus in the esophageal aperture of the diaphragm is the ligament of Morozov-Savvin (diaphragm-esophageal ligament). It resists the traction of the cardiac region upwards, allowing movement in the esophagus at the time of swallowing, coughing, vomiting. Fixation of the esophagus also contributes to the peritoneum: on the right abdominal esophagus is held by two peritoneal sheets forming the hepatic-gastric ligament, behind - the gastro-pancreatic fold of the peritoneum. Near-esophageal fatty tissue, gas bubble of the stomach and the left lobe of the liver also contribute to fixing the esophagus. The atrophy of muscle fibers arising in the esophageal orifice of the diaphragm, and especially the ligament of Morozov-Savvin, leads to the widening of the esophageal aperture of the diaphragm, the formation of "hernial gates," the increase in the mobility of the esophagus, and predisposes to the development of a hernia of the esophageal opening of the diaphragm.

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

Isolate congenital hernias, the formation of which is associated with uneven development of muscles and orifices of the diaphragm, incomplete gastric emptying into the abdominal cavity, obliteration of air-intestinal pockets, weakness of connective tissue in the esophageal and aortic aperture of the diaphragm. Most of the adult GADPs are acquired and are formed as a result of combined effects of various factors, of which the main role is played by the weakness of connective tissue structures and the atrophy of muscle fibers that form the esophageal aperture of the diaphragm, increased intra-abdominal pressure and upward traction of the esophagus with dyskinesia of the digestive tract and diseases of the esophagus.

According to N. Bellmann et al. (1972), GVAP is a frequent sign of generalized weakness of connective tissue (small collagenosis). It is assumed that the pathogenesis is due to insufficient absorption of ascorbic acid and a violation of collagen synthesis. Observations pointing to the frequent combinations of HAPP with hernias of other location: inguinal, umbilical, white abdominal line, varicose veins of the lower extremities, diverticulosis of the gastrointestinal tract, confirm this hypothesis.

Increase in intra-abdominal pressure is observed with pronounced meteorism, persistent constipation, pregnancy, especially repeated, indomitable vomiting, strong and persistent cough (it is known that 50% of patients with chronic obstructive bronchitis with a long history of the disease are diagnosed with GPOD), ascites, if present in the abdominal cavity large tumors, with severe degrees of obesity. Often, the hernia is formed after heavy physical exertion, especially in untrained individuals. This mechanism of development of hernias is noted in young people. Also in the pathogenesis of the formation of hernias, some authors attach importance to trauma, surgery on the abdominal cavity, in particular, resection of the stomach.

Functional disorders (dyskinesias) of the esophagus often occur with peptic ulcer of the stomach and duodenum, chronic cholecystitis, chronic pancreatitis and other diseases of the digestive system. With hypermotor dyskinesia of the esophagus, its longitudinal contractions cause the esophagus to be pulled upward and contribute to the development of GAP. Known triad Kastena (GPOD, chronic cholecystitis, ulcer 12 duodenal ulcer) and the triad Saint (GPOD, chronic cholecystitis, diverticulosis of the colon). A.L. Grebenev revealed chronic cholecystitis and cholelithiasis among patients with HFAP in 12% of cases, and duodenal ulcer in 23%.

There is no unified classification of the HVAC. According to the classification based on the anatomical features of the GPOD, a sliding (axial, axial) hernia is distinguished, characterized in that the abdominal part of the esophagus, the cardia and the fundus of the stomach can freely penetrate into the thoracic cavity through the enlarged esophageal aperture of the diaphragm and return back to the abdominal cavity. And also para-esophageal, in which the terminal part of the esophagus and cardia remain under the diaphragm, and part of the fundus of the stomach penetrates into the thoracic cavity and is located next to the thoracic esophagus. With a mixed version of the hiatus, a combination of axial and paraeophasal hernias is observed.

According to the data of X-ray manifestations, depending on the size of the prolapse (event) of the stomach in the chest cavity. Tager and A.A. Lipko (1965), distinguish three degrees of HVAC.

With the GVAP of the first degree in the chest cavity above the diaphragm is the abdominal section of the esophagus, 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 the initial hernia (displacement vertically in the norm does not exceed 3-4 cm). In the case of HFAP II degree, the vestibule and cardia lie under the diaphragm, and in the diaphragmatic foramen there are folds of the gastric mucosa. In the case of HAART of the third degree, along with the abdominal segment of the esophagus and the cardia, part of the stomach also falls into the chest cavity (body, antral section).

According to clinical classifications of GPAP (VK Vasilenko and AL Grebenev, 1978, BV Petrovsky and NN Kanshin, 1962) allocate fixed and non-fixed hernias. According to N.N. Canshin, fixation of a hernia in the mediastinum is caused not by adhesive process, but by negative intrathoracic pressure. Fixation and the magnitude of the GPAP are in feedback - the smaller the hernia, the greater its mobility and the tendency to increase and vice versa, the larger the hernia, the more often it is fixed and stable in size. Subdivide the hernia depending on the organs that make up the hernial sac (esophageal, cardiac, fundal, antral, subtotal and total gastric, intestinal, glandular), and the congenital short esophagus (thoracic stomach) is isolated. In addition, there is a classification of hernias depending on the complications arising from the presence of a hernia, the first place of which is reflux esophagitis. There is a vicious circle when GVAP leads to reflux esophagitis, and the latter promotes an increase in the hernia, due to the traction mechanism, as well as the shortening of the esophagus as a result of the cicatrical-inflammatory process.

The main role in the mechanism of cardia closure is assigned to the lower esophageal sphincter (NPS). NPS is a smooth-muscular thickening located at the junction of the esophagus into the cardiac region of the stomach 3-4 cm long, having a specific autonomous motor activity, its own innervation, and blood supply. These features make it possible 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 non-cholinergic and non-adrenergic nerve fibers. Sympathetic impulse strengthens the tone of the lower esophageal sphincter. In addition, various humoral factors influence the myogenic properties of the smooth muscles of the lower esophageal sphincter: gastrin, motilin, histamine, bombesin, vasopressin, prostaglandin F _{2 and} alpha-adrenomimetics, beta adrenoblockers - increase the tone of the lower esophageal sphincter, and secretin, glucagon, cholecystokinin, neurotensin, an inhibitory polypeptide, progesterone, prostaglandin, alpha-adrenoblockers, beta-adrenomimetics, dopamine-lower the tone of the lower esophageal sphincter. In rest, the muscular fibers of the esophagus are in a state of tonic constriction, so in a resting condition in a healthy person the esophagus is closed, while in the lower esophageal sphincter pressure is created from 10 to 30 mm Hg. Art. (depending on the phase of breathing). The minimum pressure of the lower esophageal sphincter is determined after eating, maximum at night. During swallowing movements, the tone of the muscles of the lower esophageal sphincter decreases and after passage of food into the stomach the lumen of the lower part of the esophagus is closed. With GERD hypotension occurs or even atony of the lower esophageal sphincter, pressure in the lower esophageal sphincter rarely reaches 10 mm Hg. Art.

Pathophysiological mechanisms of spontaneous (or transient) relaxation of the lower esophageal sphincter are not yet fully understood. Perhaps, this depends on the violation of the cholinergic effect or on the enhancement of the inhibitory effect of nitric oxide. In the norm of relaxation of the lower esophageal sphincter, 5-30 seconds continue. The majority of patients with GERD experience repeated episodes of spontaneous relaxation of the lower esophageal sphincter that can not be controlled adequately. Transient relaxation of the lower esophageal sphincter can be a response to incomplete swallowing, bloating, so reflux episodes often occur after eating.

Relaxation of the lower esophageal sphincter can be associated with swallowing, which is observed in 5-10% of reflux episodes, the cause of them - impaired peristalsis of the esophagus. It should be noted that modern prokinetics insufficiently effectively reduce the number of episodes of relaxation of the lower esophageal sphincter. In the long term there is yet to be deciphered the mechanisms of the regulation of the function of the lower esophageal sphincter and the introduction of new prokinetic drugs into clinical practice.

Causes that lead to more frequent episodes of spontaneous relaxation (relaxation) of the lower esophageal sphincter:

• violation of the peristalsis of the esophagus (dyskinesia of the esophagus), leading to a smoothing of the esophagogastric-gastric angle, a decrease in pressure on the lower part of the esophagus in the chest. Often this contributes to the neurotic state of the patient or such diseases as systemic scleroderma, diaphragmatic hernia;
• fast, and plentiful food, 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 casting the contents of the stomach into the esophagus;
• vetiorism;
• ulcer disease (especially with ulcer localization in the duodenum), with gastroesophageal reflux observed in 1/2 patients;
• duodenostasis of any etiology;
• excessive consumption of fatty meat, refractory fats (lard), flour products (pasta, vermicelli, sweet biscuits, bread), spicy seasonings, fried foods (these types of food contribute to a prolonged delay of food masses in the stomach and increase in intra-abdominal pressure).

These factors cause the casting of gastric or duodenal reflux, containing aggressive factors - hydrochloric acid, pepsin, bile acids, which causes damage to the mucosa of the esophagus. Such damage develops with a prolonged contact of refluxate (more than 1 hour a day) with the mucosa of the esophagus, as well as inadequate functioning of protective mechanisms.

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

The esophagus is continuously cleaned by swallowing saliva, eating food and liquids, secretion of the glands of the esophagus submucosa and gravity. With GERD, long-term exposure of aggressive gastric contents to the mucosa of the esophagus is observed, a decrease in the activity of esophageal clearance and lengthening of its time (in the norm it averages on average 400 s, with gastroesophageal reflux disease of 600-800 s, that is, it is almost doubled) . It occurs as a result of esophageal dissotorics (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 an esophagogue reflex that is disrupted 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, salivary gland diseases, radiation therapy for tumors in the head and neck region, and treatment with anticholinergics.

The resistance of the mucosa of the esophagus is determined by a protective system consisting of three main parts:

• pre-epithelial protection (salivary glands, esophageal submucosa glands), including mucin, non-mammalian proteins, bicarbonates, prostaglandin E ₂, epidermal growth factor;
• epithelial protection - normal regeneration of the mucosa of the esophagus, which can be divided into structural (cell membranes, intercellular connective complexes) and functional (epithelial transport Na ⁺ / H ⁺, Na ⁺ -dependent transport CI- / HCO3, intracellular and extracellular buffer systems, cellular proliferation and differentiation);
• post-epithelial protection (normal blood flow and normal tissue acid-base balance).

Based on the foregoing, it can be argued that GERD occurs when the balance between aggressive gastric contents factors and defense factors with a distinct predominance of aggression factors is disturbed.

[1], [2], [3]