Diagnosis and treatment of patients with recurrent gastroduodenal hemorrhage - Shaprynskyi V.O. 2009

Pathogenesis of recurrent gastroduodenal hemorrhage in patients with peptic ulcer disease

The Pathogenesis of recurrent gastroduodenal bleeding in patients with PEPTIC ULCER DISEASE is multifaceted and not always straightforward. To date, several questions remain unresolved regarding the pathogenesis, onset, and progression of peptic ulcers, as well as The Development of early recurrent bleeding. It is evident that ulceration is The final stage of a complex, multicomponent pathological process involving genetic factors, Autonomic Nervous system regulation, METABOLISM/18.html">The Influence of biogenic amines, gastrointestinal Peptide Hormones, and bacterial expansion. This disrupts the balance between the protective mechanisms of the gastroduodenal mucosa and aggressive factors.

Several theories have been proposed to explain the occurrence of recurrent bleeding; however, they cannot always account for recurrent Hemorrhage in a specific patient. Many of these theories compete with or even contradict one another.

Significant advances in understanding the recurrence of peptic ulcer-induced gastrointestinal bleeding allow for the Classification of the following theories regarding its occurrence:

1. The aggressive acid-peptic factor theory, which posits acid and Pepsin as causes of clot lysis and subsequent recurrent bleeding.

2. The Theory of Helicobacter pylori infection of the mucosa.

3. The theory of intravascular clot Fibrinolysis driven by increased Blood fibrinolytic activity and the development of DIC syndrome in these patients.

4. The theory of intensified alterative processes secondary to progressive tissue Hypoxia within the ulcer bed.

5. The theory of a specific pathomorphological substrate developing in the ulcer base of patients with recurrent peptic ulcer-induced gastrointestinal bleeding.

6. The theory of autoimmune aggression development.

7. The theory of functional Disorders of the endocrine (APUD) System of the gastric and duodenal mucosa.

8. The theory of gastrointestinal bleeding and its recurrence as a genetically determined factor in patients with peptic ulcer disease.

9. The theory of hyperdynamic enhancement of local blood flow.

10. The mechanical theory.

The aggressive acid-peptic factor theory, which posits acid and pepsin as causes of clot lysis and subsequent recurrent bleeding. Hypersecretion of Hydrochloric acid and pepsin is considered a key factor in ulcerogenesis. On one hand, increased production of hydrochloric acid and pepsin is genetically determined (increased parietal Cell mass, elevated gastrin secretion in response to food stimulation, and higher serum pepsinogen-1 levels); on the other hand, it is linked to impaired neuroendocrine regulation (increased vagal tone, hyperplasia, and hyperfunction of G- and ECL-Cells). In vitro studies have shown that acid adversely affects Blood Coagulation and platelet aggregation, playing an important role in clot lysis. A platelet plug formed during vascular injury can independently provide adequate hemostasis. Subsequently, this clot undergoes retraction and degradation. A decrease in pH impairs platelet aggregation, while gastric juice significantly enhances fibrinolysis. This effect of gastric juice is mediated by pepsin, whose proteolytic activity is directly dependent on the pH of the medium, peaking at pH 1,6. When pH increases to 4,0, pepsin loses its activity, thereby reducing the risk of clot lysis. It should also be noted that environmental pH affects prothrombin time, and thus, the time required for clot formation.

When the balance between protective and aggressive factors is disrupted, ulceration occurs, during which the vascular wall may be involved in the destructive process, leading to hemorrhage. The clot formed upon vascular injury is covered with mucus, which is a component of the mucus-bicarbonate barrier and plays a major role in the mechanical Protection of the gastric and duodenal mucosa. Pepsin exerts a mucolytic effect, destroying the protective mucus layer. Inhibiting acidity has a favorable effect on preserving the mucus-bicarbonate barrier and prevents clot destruction. Thus, by monitoring and controlling intragastric pH, clot lysis can be largely prevented, thereby avoiding recurrent ulcer bleeding. However, the number of studies measuring gastric pH at the peak of ulcer bleeding is very limited, and their results remain controversial.

Contrary to this theory, the occurrence of recurrent bleeding in elderly patients, who predominantly present with achylia, remains unexplained. Furthermore, recurrence still occurs even when medical achylia is achieved.

The theory of Helicobacter pylori infection of the mucosa. Among the alterative (damaging) factors of the gastric and duodenal mucosa is the presence of a pathogenic strain of Helicobacter pylori, which is detected in 94,5-96,3 % of patients. Studies by T. Matsubisa (2002) and M.E. Van Leerdam et al. (2002) showed that the H. pylori infection rate increases from 72,3 % in uncomplicated peptic ulcer disease to 98,1 % in cases of bleeding. When examining the infection rate across age groups, it decreases with advancing age, though it remains high. H. pylori can penetrate the interepithelial space and enter epithelial cells, causing inflammatory Changes in the mucosa and reducing mucus production. Consequently, the mucosa loses its protective properties against aggressive factors in the gastric content, leading to The formation of erosions and ulcer defects. Helicobacter infection also impairs the physiological regeneration of the mucosa. However, authors such as N.D. Yushchuk et al. (202), E.M. Lipitsky et al. (2005), and R. Colin et al. (2001) argue that the infectious concept does not fully explain the occurrence of recurrent duodenal bleeding.

The theory of intravascular clot fibrinolysis driven by increased blood fibrinolytic activity and the development of DIC syndrome in these patients. The onset of bleeding leads to disturbances in central hemodynamics and various homeostatic parameters. Specifically, There is a decrease in Hemoglobin and red blood cell count, and the development of hypoalbuminemia, reduced partial pressure of oxygen in the blood, and metabolic acidosis. In light of this, some researchers have theorized that clot lysis in the Vessels of the Stomach and duodenum may occur under the Influence of the fibrinolytic system activated after the primary hemorrhage, thereby causing recurrent bleeding. However, other researchers, having conducted thorough investigations, demonstrated that primary bleeding is accompanied by a decrease in activated partial thromboplastin time (aPTT), prothrombin time, and euglobulin clot lysis time, indicating a reduction in the blood's fibrinolytic activity. At the current level of understanding, these changes can be interpreted as hypercoagulation syndrome. On the other hand, in patients with ongoing bleeding, an increase in activated recalcification time, fibrinogen concentration, and soluble fibrin monomer complexes was also detected, pointing rather to the hypercoagulative phase of DIC syndrome. Therefore, there is very little evidence supporting such a mechanism for recurrent bleeding in the early post-hemorrhagic period. Nevertheless, indicators of the hypocoagulative phase of DIC syndrome—characterized by prolonged aPTT and prothrombin time, decreased platelet count and activity, a sharp increase in fibrinolytic activity, and elevated levels of fibrinogen degradation products—are observed on average 2-5 days after the primary hemorrhage. Thus, this mechanism of recurrent bleeding should not be entirely dismissed.

The theory of intensified alterative processes secondary to progressive tissue hypoxia within the ulcer bed. V.K. Gostishchev et al. (2004) consider ischemic changes in the mucosa to be the key factor in the onset of ulcer bleeding. Based on a comparative Analysis of the microscopic picture, oxygen status, and integral Redox Potential of gastroduodenal ulcers during recurrent bleeding and when it is threatened, they established that recurrent ulcer bleeding is driven by progressive ischemic necrosis in the periulcerous zone. These processes are caused by severe Circulatory Disorders in the gastric and intestinal walls during acute hemorrhage. It has been shown that a decrease in systolic blood pressure to 70 mmHg leads to a 33% reduction in gastric wall blood flow, which in turn reduces the oxygenation of the respective Tissues by 40-60%.

Thus, necrosis develops against a Background of local hyperfunction resulting from both systemic hemodynamic disturbances caused by acute blood loss syndrome and chronic ischemia caused by the ulcer process itself. In other words, recurrent bleeding develops due to ischemic necrosis of tissues located deep within the periulcerous zone, including ischemic Necrosis of the walls of large vessels in the muscular and elastic layers.

This theory is also supported by V.V. Makarov (2002), who, during an ultramicroscopic Study of the bleeding ulcer zone, observed microcirculatory bed impairment, destruction of outer mitochondrial membranes, and destruction of a significant portion of The Cell against a background of reduced mucoid secretion and hydrochloric acid hypersecretion.

O.I. Ivashchuk and V.Yu. Bodyaka (2004) investigated the vascular architecture of the duodenum in deceased patients with bleeding peptic ulcers and compared these data with patients without gastrointestinal pathology. They established that in duodenal ulcer bleeding, there is a large vessel caliber, a poorly developed vascular network, straight courses of small Arteries, and an absence of a diffuse pattern of blood supply. These architectural features must be taken into account during endoscopic hemostasis and Surgical Treatment.

A number of foreign authors, including J.J. Farre et al. (2000), L. Rachlin et al. (2001), A. Baranovsky et al. (2001), D. Felmeden et al. (2003), and O.A. Carretero et al. (2005), confirm The Role of the ischemic factor in the occurrence of recurrent bleeding from duodenal ulcers, supplementing it with generalized atherosclerosis in individuals over 60 years of age and congenital underdevelopment of the capillary network. However, despite all of the above, it remains unclear why an ulcer in the ulcerogenic zone can heal and then suddenly recur.

The theory of a specific pathomorphological substrate developing in the ulcer base of patients with recurrent peptic ulcer-induced gastrointestinal bleeding.

The identification of certain morphological features of bleeding gastroduodenal ulcers complicated by acute recurrent hemorrhage suggests the potential existence of a specific morphological substrate in ulcers complicated precisely by recurrent GIB. Thus, histopathological examination of gastric and duodenal ulcer substrates revealed A large number of lymphoid aggregates in 86% of patients, along with significant lymphoid infiltration of this area, leading to rigidity of the organ wall. On the other hand, examination of the vascular bed of the ulcer substrates revealed arterial intimal hyperplasia and fibrosis of the vascular muscular layer with lumen obliteration. This occurred against a background of impaired vascular permeability, manifested as numerous hemorrhages in the mucosal and submucosal layers, areas of fibrinoid necrosis, and paretic dilation of Veins and venules with the formation of erythrocyte-fibrin thrombi. All of this suggests that recurrent ulcer bleeding occurs similarly to parenchymal hemorrhage, where the vessel wall is fixed to surrounding tissues that prevent it from collapsing, thereby disrupting the physiological processes of thrombus formation.

The theory of autoimmune aggression development.

An Analysis of certain hematological parameters in patients with recurrent GIB of ulcer Etiology revealed that patients develop signs of endogenous intoxication, as confirmed by LII, MSM, and urea levels. The occurrence of endogenous intoxication is associated not only with the severity of blood loss but also with the presence of Shock upon admission. Higher indicators of endogenous intoxication were observed in patients with ongoing bleeding at the time of hospitalization, i.e., patients admitted in a state of shock. Indicators of endogenous intoxication clearly correlate with the body's immunological status. As the severity of blood loss increases, there is a decrease in the proportion of B- and T-lymphocytes and T-helpers in the blood, which can be logically explained by the loss of formed blood elements; however, the level of T-suppressors, on the contrary, increases, indicating a disruption of cellular Immunity in acute recurrent GIB of ulcer etiology, manifested as an increase in cells that inhibit cellular immunity. This is also indicated by the T-helper/T-suppressor ratio, which decreases as blood loss severity increases, approaching 1 in grade III blood loss. Investigation of immunoglobulin levels revealed distinct dysimmunoglobulinemia: a decrease in IgA levels was noted with increasing blood loss, while IgM and IgG levels, conversely, increased. Based on this, it can be concluded that there is a significant impairment of humoral immunity in patients with recurrent GIB of ulcer etiology. According to our study, these pathological changes are significantly aggravated by the presence of hemorrhagic shock at the time of examination, which, in other words, indicates the occurrence of recurrent bleeding.

Against the background of such severe impairments of systemic immunity, the state of local immunity of the gastric and duodenal mucosa, as well as the level of anti-organ Antibodies, was studied in patients with peptic ulcer disease complicated by GIB. It was found that in patients with gastric and duodenal ulcers, the antibody titers against the vascular wall, gastric and duodenal mucosa, and Liver were significantly higher than those in patients with uncomplicated peptic ulcer disease. At the onset of recurrent bleeding, antibody levels against the vascular wall and the gastric and duodenal mucosa increased 4-8 fold. Concurrently, a decrease in IgA levels on the gastric and duodenal mucosa was noted, indicating a decline in mucosal immunity.

The theory of endocrine (APUD) system dysfunction in the gastric and duodenal mucosa.

Gastrointestinal Hormones are involved in The regulation of hydrochloric acid secretion. It is the coordinated interaction within the neuroendocrine system that maintains the balance between the factors of 'aggression' and 'defense' of the gastroduodenal mucosa. Gastrin, produced by G-Cells of the gastric antral mucosa, stimulates hydrochloric acid secretion. Blood gastrin levels depend on the severity of the inflammatory process in the gastric mucosa, intragastric acidity, the action of physiological stimulants, and neural factors. Increased gastrin production can occur As a result of the action of inflammatory cytokines on G-cells. The action of pro-inflammatory cytokines is mediated by inhibiting D-cells, which secrete the gastrin antagonist Somatostatin. Thus, the inflammatory process in the gastroduodenal mucosa, the action of Immune Response regulators (cytokines), and the function of mucosal endocrine cells (APUD system), which are important regulators of digestive tract function, are linked together.

Studies conducted by N.K. Malinovska et al. (2006) revealed a disruption in The ratio of G and D cells, meaning that 'aggression' factors outweigh mucosal 'defense' factors even after comprehensive treatment during the stage of clinical and endoscopic remission.

O.V. Orlovskyi (2006) studied IL-4, the level of which depended on the presence of ulcer bleeding. Interestingly, IL-8 stimulates gastrin production by G-cells, thereby increasing gastric acid production.

Studies by V.D. Seidov et al. (2002) and A.V. Alekberadze (1999) demonstrated a significant role of the APUD system function in the occurrence of ulcer bleeding. The level of secretory activity of apudocytes and The Nature of their interaction are of prognostic value. The combination of hyperplasia and hyperfunction of G and ECL apudocytes in patients with peptic ulcer disease complicated by bleeding is stable and irreversible, carrying prognostic significance, which underscores the relevance of further research in this direction.

The theory of GIB and its recurrence as a genetically determined factor in patients with peptic ulcer disease.

Studies by V.P. Ivanov et al. (2006) have proven that the IL-1R Gene mutation can be considered a genetic marker for the development of gastrointestinal bleeding. The authors recommend using this fact to predict the course of the disease and select treatment strategies.

The theory of hyperdynamic enhancement of local Circulation.

This theory is based on the occurrence of a so-called 'hypertensive crisis' in the celiac trunk territory, which leads to the displacement of a thrombus from an eroded vessel, or damage to another part of the vessel involved in the ulcer crater.

Mechanical theory.

Statistical analysis of our data, comprising 1,500 inpatient medical records of patients with peptic ulcer disease complicated by gastrointestinal bleeding, showed that recurrent bleeding occurred in 255 patients. In 59.4% (142) of patients with ARGIB, recurrent bleeding occurred after getting out of bed in 92 patients, including in the restroom in 48 patients. Against the background of vomiting gastric contents, it occurred in 13.8% (33) of patients. Therefore, from our perspective, it is extremely important in the treatment of patients with GIB of ulcer etiology to maintain strict bed rest for at least 3-5 days, as well as to insert a nasogastric tube—not so much for the early Diagnosis of recurrent bleeding (which has a 30% error rate), but for gastric decompression and the Prevention of hyperperistaltic gastric spasms.

Certainly, isolating any single theory and claiming that recurrent bleeding occurs solely due to it would be incorrect. The combination of all the aforementioned factors genetically determines and causes profound pathological changes in the wall of The Stomach and duodenum, serving as the background for the development and recurrence of bleeding. Meanwhile, the mechanical theory and the theory of the so-called 'hypertensive crisis' appear to be the triggers for recurrent hemorrhage.