Pathogenetic mechanisms: NSAIDs and stress
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is one of the main causes of gastric mucosal damage. Classical drugs inhibit not only the target COX-2 (which provides the anti-inflammatory effect) but also COX-1. This blocks the production of prostaglandins, which are critically important for mucosal regeneration. Second-generation selective NSAIDs lack this side effect as they do not affect COX-1.
True stress ulcers develop through a different scenario. Severe stress stimulates the vagus nerve (n. vagus), causing a surge in adrenaline and ACTH. This leads to a sharp spike in hydrochloric acid secretion against the background of mucosal ischemia, which destroys the protective mucosal-epithelial barrier. In practice, patients often present with a combination of stress, H. pylori infection, and NSAID use, making it crucial for the physician to identify the leading cause.
Eponymous syndromes and systemic diseases
Symptomatic ulcers often accompany severe systemic conditions and endocrine disorders:
- Cushing ulcers: multiple defects in traumatic brain injuries, hemorrhages, and neurosurgical interventions. The cause is acid hypersecretion due to high vagal tone.
- Curling ulcers: develop in extensive burns (burn disease). Ischemia and tissue acidosis drastically reduce the protective properties of the mucosa.
- Zollinger–Ellison syndrome: a manifestation of multiple endocrine neoplasia (MEN) type I. A gastrin-producing tumor (gastrinoma) forces the stomach to produce extreme amounts of acid.
- Polycythemia vera (Polycythemia rubra vera): increased blood viscosity and protein precipitation disrupt microcirculation, blocking epithelial renewal.
- Diabetes mellitus: systematically reduces tissue repair capabilities, while concurrent H. pylori gastritis often acquires an autoimmune damage pattern.
Infections and comorbid conditions
In addition to classical H. pylori (and the related Helicobacter heilmannii), ulcers may be associated with viral infections. Herpes simplex virus type 1 (HSV-1) can persist in vagal ganglia, disrupting mediator secretion and cellular renewal. Cytomegalovirus (CMV) is frequently found in immunosuppressed patients (HIV, radiation sickness, glucocorticoid therapy), and its histological marker at the ulcer edges is "owl's eye" cells.
In renal failure, the barrier suffers due to a complex of factors: from stress-induced glucocorticoid release to hypergastrinemia, secondary hyperparathyroidism, and protein malnutrition. In primary generalized amyloidosis, protein is deposited in blood vessels, causing their stenosis and ischemia of the gastric wall. Liver cirrhosis also promotes ulceration due to the high prevalence of H. pylori and elevated nitric oxide levels, which trigger cellular apoptosis.
Morphogenesis and the "rail-layer effect"
The pathological process begins with acute erosion—the loss of the mucus-producing epithelium, as a result of which the lamina propria (lamina propria) is exposed to the aggressive action of pepsin, hydrogen protons, and chloride ions. Upon transition into chronic erosion, a zone of fibrinoid necrosis appears on the surface, but granulation tissue is still absent.
The formation of a full-fledged chronic ulcer is invariably accompanied by chronic inflammation, which prevents the epithelium from realizing its high regenerative potential. Healing (re-epithelialization) proceeds according to the "rail-layer effect" principle:
- Epitheliocytes synthesize type IV collagen to create their own basement membrane.
- Cells migrate along this pathway, crawling over the defect.
- The basement membrane fuses with the stroma (where types I and III collagens predominate) with the help of type VII collagen.
A critical condition for this process is the cleansing of the ulcer base from exudate and fibrinoid necrosis. In the periulcerative zone, a special clone of cells temporarily appears—UACL (ulcer associated cells lineage). They originate from stem cells of the glandular isthmus and operate under the strict control of myofibroblasts, disappearing immediately after defect closure.
Clinical presentation
The leading symptom of the disease is epigastric pain (pain in the upper abdomen). It has a clear relationship with meals: it may occur immediately after eating, 2–3 hours later, or on an empty stomach (including characteristic nocturnal pain).
The pain syndrome is often accompanied by various dyspeptic disorders. Marked seasonality with exacerbations in spring and autumn is typical for the disease course.
Briefly: answers to topical questions
What are the macroscopic features of a chronic gastric ulcer during an exacerbation?
Macroscopically, a chronic gastric ulcer during exacerbation presents as an oval or round defect ranging from several millimeters to 1–2 cm in size.
- Mucous membrane — folds converge toward the defect area.
- Ulcer edges — asymmetric: the edge facing the cardia is undermined, while the one facing the pylorus is sloping.
- Ulcer base — smooth or covered with a gray coating, may contain an eroded blood vessel.
During the exacerbation period, centrifugal growth of the ulcer is observed, wherein the necrosis zone expands, capturing the edges and penetrating deep into the scar.
Which layers (zones) are distinguished in the base of a chronic ulcer upon microscopic examination?
Upon microscopic examination, four consecutive zones are distinguished in the base of a chronic ulcer:
- Zone of exudation — fibrinous-purulent exudate.
- Zone of fibrinoid necrosis — an area of destroyed tissue lacking the collagens necessary for repair.
- Zone of granulation tissue — tissue covered by regenerative epithelium after cleansing.
- Zone of fibrosis — fibrous connective (scar) tissue.
Signs of exacerbation correlate with an increase in the zones of fibrinoid necrosis and exudation, whereas signs of remission correlate with the predominance of granulation and scar tissue.
What are the classical complications of symptomatic gastric ulcers?
Classical complications of secondary (symptomatic) acute gastric ulcers include hemorrhage and perforation of the organ wall.
- Vascular erosion — leads to gastrointestinal bleeding.
- Perforation — rupture of the hollow organ wall (particularly characteristic of steroid ulcers).
In the case of chronization, complications such as penetration (when the ulcer base becomes the wall of an adjacent organ) and gastric outlet stenosis are also distinguished.
For memorizing eponymous stress ulcers: Cushing — Cranial trauma (brain), Curling — Campfire (extensive burns).
Class and exam questions
What is the morphological difference between acute and chronic erosion?
Acute erosion is a superficial defect without epithelium. In chronic erosion, a zone of fibrinoid necrosis appears on the surface, whereas granulation tissue characteristic of an ulcer is absent.
What is UACL and what is its role?
UACL (ulcer-associated cell lineage) is a temporary clone of cells from the glandular isthmus. It ensures regeneration under the control of myofibroblasts and completely disappears after the ulcer defect closes.
Why is clearance from necrosis so important for ulcer healing?
In the zone of fibrinoid necrosis, there are no collagens necessary for epithelial attachment. Without cleansing the ulcer base, the basement membrane (type IV collagen) cannot bind to the stroma (types I and III collagens) via type VII collagen.
What else to study on this topic
- Pathogenesis of ulcers in renal failure: the role of hypergastrinemia and secondary hyperparathyroidism.
- Mechanisms of mucosal damage in liver cirrhosis: the effect of nitric oxide and free radicals.
- Tumor processes and ulceration: giant ulcers in lymphomas and pancreatic cancer invasion.
- The effect of hypercalcemia on cholinergic hydrochloric acid secretion.
- Methods for detecting viral agents (HSV-1, CMV) in biopsy specimens: IHC, PCR, and in situ hybridization.
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