Causes and pathogenesis of peptic ulcer disease

Many theories have been proposed for the development of peptic ulcer disease (inflammatory-gastritis, cortico-visceral, neuro-reflex, psychosomatic, acidopeptic, infectious, hormonal, vascular, immunological, traumatic), but none of them fully accommodates the changes that are realized in the form of an ulcerative defect of the mucous membrane of the stomach and duodenum. In this regard, peptic ulcer disease is considered a polyetiological disease with heterogeneity of genetic predisposing factors.

There are a number of the most important etiological factors in the development of peptic ulcer disease:

• hereditary-genetic;
• neuropsychiatric (psychotrauma, persistent stress, including family conflicts);
• neuroendocrine;
• alimentary;
• infectious;
• immune.

The following factors predispose to the development of peptic ulcer disease in children:

1. Helicobacter pylori infection. In children with peptic ulcer disease, Helicobacter pylori is present in the mucous membrane of the antrum of the stomach in 99% of cases and in the mucous membrane of the duodenum in 96% of cases;
2. early transfer to artificial feeding, which induces an increase in G (gastrin-producing) and H (histamine-producing) cells of the mucous membrane of the antral part of the stomach;
3. alimentary errors;
4. long-term use of certain medications (salicylates, glucocorticoids, cytostatics, etc.);
5. features of family life - organization of everyday life and upbringing of children, family features of nutrition, relationships in the family;
6. physical inactivity or physical overload;
7. foci of chronic infection;
8. intestinal parasitosis;
9. neuropsychic overload;
10. smoking and substance abuse;
11. food allergies.

Genetic predisposition to peptic ulcer disease is realized by increasing the synthesis of hydrochloric acid in the stomach (genetically determined increase in the mass of parietal cells and hyperactivity of the secretory apparatus), increasing the content of gastrin and pepsinogen (increased concentration of serum pepsinogen I, inherited in an autosomal dominant manner and found in 50% of patients with peptic ulcer disease). In patients with peptic ulcer disease, a defect in the formation of mucus in the inner lining of the stomach and duodenum is diagnosed, expressed by a deficiency of mucopolysaccharides, including fucoglycoproteins, syndrochondroitin sulfates and glucosaminoglycans.

A certain influence on the formation of an ulcerative defect is exerted by a violation of the motility of the upper gastrointestinal tract in the form of stagnation of acidic contents or acceleration of evacuation from the stomach into the duodenum without adequate alkalization of the acid.

As a result of examination of the genetic status of patients with peptic ulcer disease by 15 systems of phenotypic polymorphism, it was found that duodenal ulcer disease more often develops in those with blood group 0(1), Rh-negative and phenotype Gml(-). On the contrary, those with blood group B(III), Rh-positive, Lewis ab- and phenotype Gml(+) usually do not suffer from duodenal ulcer disease. An important factor in the genetic determination of peptic ulcer disease is impaired blood supply to the gastric mucosa (mainly the lesser curvature) and the duodenal bulb.

Clinical and genealogical analysis of the pedigrees of children with duodenal ulcer disease showed that the hereditary predisposition to gastrointestinal pathology was 83.5%. Including more than half of the children had a burdened heredity for gastric ulcer disease and duodenal ulcer disease.

Neuropsychiatric disorders affecting the immune system play an important role in the development of peptic ulcer disease. The influence of the stress factor was found in 65% of Helicobacter-positive and 78% of Helicobacter-negative children with peptic ulcer disease.

Neuroendocrine factors are realized through the mechanisms of the APUD system (gastrin, bombesin, somatostatin, secretin, cholecystokinin, motilin, enkephalins, acetylcholine). Gastrin is an intestinal hormone produced by G cells of the stomach under the influence of acetylcholine (characterizes the action of the vagus nerve), products of partial hydrolysis of food proteins, a specific "gastrin-releasing peptide" (bombesin) and stretching of the stomach. Gastrin stimulates gastric secretion (exceeds histamine by 500-1500 times), promotes hyperplasia of the fundic glands of the stomach, has an ulcer-protective effect. Hyperproduction of gastrin or histamine can be a sign of Zollinger-Ellison syndrome, mastocytosis.

Acetylcholine also serves as an inducer of increased histamine production by ECL cells (Enterochromaffin-Hke cell), which leads to hypersecretion and hyperacidity of gastric juice and a decrease in the resistance of the gastric mucosa to acidopeptic aggression.

Somatostatin inhibits gastric secretion by suppressing the production of gastrin by G cells, increasing the volume of bicarbonate production by the pancreas in response to a decrease in pH in the duodenum.

The role of melatonin in the development and course of the ulcer process is being studied. Melatonin is a hormone of the pineal gland (pineal body), also synthesized by enterochromaffin cells (EC cells) of the gastrointestinal tract. Melatonin has been proven to participate in the regulation of the body's biorhythms, antioxidant and immunomodulatory effects, influence on the motility of the gastrointestinal tract, microcirculation and proliferation of the mucous membrane, and the ability to inhibit acid formation. Melatonin affects the gastrointestinal tract both directly (interacting with its own receptors) and by binding and blocking gastrin receptors.

The pathogenesis involves not only an increase in the secretion of intestinal hormones, but also genetically determined hypersensitivity of parietal cells to gastrin and histamine.

Alimentary factors are realized when the diet is violated: irregular meals, consumption of fried, smoked foods, use of products with a high content of salt, extractive substances, preservatives, flavor enhancers.

The main factor of chronic ulcerogenesis is considered to be inflammation of the gastroduodenal mucosa caused and maintained by H. pylori. Data are regularly published that peptic ulcer disease is a gastritis-associated disease. H. pylori contacts cytokines secreted by various epithelial cells of the mucosa, primarily with interleukin 8, which changes the parameters of chemotaxis, chemokinesis, aggregation and release of lysosomal enzymes from neutrophils. The occurrence or recurrence of peptic ulcer disease can be caused by the continued impact of altered signaling systems launched by H. pylori, even if the pathogen has been eradicated.

The pathogenesis of duodenal ulcer disease is still poorly understood. The concept of a shift in balance between aggressive and protective factors, which causes damage to the mucous membrane, is relevant. Aggressive factors include the acid-peptic factor and pyloric helicobacteriosis, and protective factors include gastric and duodenal mucus (glycoproteins, bicarbonates, immunoglobulins, etc.), high reparative activity of the mucous membrane, provided there is adequate blood supply.

Most researchers agree that individual differences in the components of natural resistance make it possible to neutralize or reduce the “aggressiveness” of a particular risk factor (genetic predisposition, imbalance between aggressive or protective factors), as well as to inactivate the effects of triggers that, in isolation, are not capable of leading to the development of peptic ulcer disease.

The significant role of autonomic imbalance in the development of peptic ulcer disease has been proven (provocation of changes in homeostasis, increased intensity of local aggressive factors and decreased protective properties of the mucous barrier, hyperhemocoagulation, decreased immunological resistance and activation of local microflora, impaired motility).

Residual organic background and/or psychotraumatic situations (depression) through increased tone of the parasympathetic nervous system lead to gastric hypersecretion and formation of an ulcer defect in the duodenum. In turn, long-term course of ulcer disease of the duodenum contributes to the formation of psychoemotional disorders, including depression, progression of vegetative disorders in the serotonin system, aggravating the course of the pathological process. Ulcer formation is promoted by both vagotonia (by stimulating gastric secretion) and sympathicotonia (impaired microcirculation in the organ wall).

Congenital hyperplasia of gastrin-producing G cells in the antrum of the stomach and duodenum contributes to hypergastrinemia and gastric hypersecretion with subsequent formation of an ulcerative defect in the duodenum.

Colonization of the antrum of the stomach by H. pylori in a patient with increased sensitivity leads to the development of G-cell hyperplasia, gastric hypersecretion, gastric metaplasia in the duodenum and the formation of an ulcer defect. The possibility and consequences of colonization of the gastric and duodenal mucosa by H. pylori depend on the characteristics of the macroorganism, including the state of the immune system, the characteristics of the H. pylori strain (pathogenicity factors).

The influence of immune factors on the development of peptic ulcer disease is caused by both defects in the body's immune reactivity (hereditary or acquired) and the impact of H. pylori pathogenicity factors, and disruption of the biocenosis of the upper gastrointestinal tract.

Studies of the immune system in children with duodenal ulcer disease associated with H. pylori infection have demonstrated immune status disorders caused by an imbalance in the cytokine system (interleukins 1, 4, 6, 8, 10 and 12, transforming growth factor-beta, interferon-y), an increase in the content of IgG antibodies to tissue and bacterial antigens, and increased production of active forms of duodenal ulcer disease by neutrophils. The production of IgG antibodies to tissue structures (elastin, collagen, denatured DNA) and gastrointestinal tissue antigens (stomach, small and large intestine, pancreas) detected in children can be considered a sign of autoimmune genesis of the disease exacerbation. The production of autoantibodies to gastric tissues during H. pylori infection has also been proven in adults. Increased production of reactive oxygen species by neutrophils in children with duodenal ulcer indicates the participation of toxic substances secreted by neutrophils in the destructive process.

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