4. Peptic Ulcer Disease: Causes and Mechanisms

Diseases of the Stomach

• This presentation covers diseases of the stomach.
• The learning objectives include applying knowledge of GI anatomy, histology, and physiology; describing the pathophysiology of acute and chronic gastritis; identifying features of H. Pylori infection; defining peptic ulcer disease (PUD); and recognizing differences between duodenal and gastric ulcers.

Acute Gastritis

• Inflammation of the gastric mucosa
• Characterized by the presence of neutrophils (white blood cells)

Gastropathy

• Stomach dysfunction
• Absence of inflammatory cells
• Often results from NSAIDs, alcohol, or bile

Gastritis

• Gastric pH = 1
• Foveolar cells produce mucus and phospholipids to protect the epithelial cells.
• Neutral pH fluid protects epithelial cells.
• NSAID, COX-1 and COX-2 can decrease stomach pH
• Uremia or H. Pylori (urease) increase ammonia and decrease H3CO2.
• Lamina propria edema, and vascular congestion cause damage.
• Erosion (loss of mucosa) with neutrophils, pus, and fibrin = hemorrhagic erosive gastritis

Mechanisms of Injury

• NSAIDs inhibit the synthesis of prostaglandins.
• NSAIDs affect all protective barriers.
• NSAIDs reduce acid secretion in the stomach.
• COX-2 inhibitors can cause stomach inflammation.
• Ammonia from uremia or H. pylori inhibit gastric bicarbonate transporters.
• Reduced mucin and bicarbonate secretion occurs in older adults with gastritis.
• Decreased oxygen delivery may exacerbate gastritis, particularly at high altitudes.

Morphology (Gastritis)

• Neutrophils are above the basement membrane and within contact with epithelial cells.
• Inflammation signifies active inflammation.

Morphology (Gastropathy)

• There is hyperplasia (increase in size) of foveolar mucus cells, typically present.
• The surface epithelium (a type of cell) is usually intact.
• Neutrophils, lymphocytes, and plasma cells are less prominent.

Helicobacter Pylori Gastritis

• Four features are linked to H. pylori virulence:
  • Flagella: allows bacteria to move in mucus
  • Urease: creates ammonia that elevates pH in the stomach
  • Adhesion molecules: help bacteria adhere to cells
  • Toxins: may contribute to ulcer development, e.g., CagA (cytotoxin-associated gene A)
• Morphology: Features found in a stomach biopsy with Helicobacter Pylori infection include a higher concentration of mucus overlying epithelial cells, neutrophils within the lamina propria, and the bacteria adhering to the surface of gastric cells.

Chronic Gastritis

• H. Pylori likely causes autoimmune atrophy in a small subset of cases (10%). Other cases involve bile reflux, mechanical causes and ulcerative lesions.
• Nausea and epigastric pain are common symptoms.
• Antral area infection may cause duodenal ulcers.
• Body or fundus infection may lead to multifocal atrophy, reduced parietal cells, reduction in stomach acid and an increase in the risk of gastric cancer.

Stress-Related Mucosal Disease

• Occurs in patients with severe trauma, extensive burns, intracranial disease, or major surgery.
• More than 75% of critically ill patients develop visible gastric lesions within 3 days.
• Commonly caused by stress, shock, sepsis, or severe trauma.
• Curling ulcers appear in the proximal duodenum in patients with severe burns or trauma.
• Cushing ulcers appear in the stomach, duodenum, or esophagus in the presence of intracranial disease.
• Characterized by high incidence of perforation.
• Pathogenesis is usually due to local ischemia caused by hypotension or reduced blood flow, as well as the release of endothelin-1.
• Cushing ulcers are thought to be caused by direct stimulation of vagal nuclei, which results in hypersecretion.
• Systemic acidosis contributes in mucosal injury due to lowering the intracellular pH.

Autoimmune Gastritis

• Less than 10% of chronic gastritis cases.
• Characterized by sparing of the antrum and causing hypergastrinemia.
• Antibodies to parietal cells and intrinsic factor are present.
• Reduced serum pepsinogen I levels (loss of chief cells), antral endocrine cell hyperplasia, and vitamin B12 deficiency lead to pernicious anemia.
• Impaired gastric acid secretion leads to achlorhydria (absence of hydrochloric acid).

H. Pylori Gastritis vs. Autoimmune Gastritis

• Key differences in presentation, location, inflammatory infiltrate, acid production, and presence of other lesions, between H. Pylori and autoimmune gastritis are summarized.
• Autoimmune gastritis is characterized by diffuse damage of oxyntic mucosa, in body and fundic areas.

Polyps

• Over 75% of gastric polyps are considered hyperplasic or inflammatory, which are often linked to H. Pylori infections.
• Polyps lasting 5-6 years or with a size over 1.5cm are typically resectable.
• Multiple polyps, smooth or eroded, often occur due to familial adenomatosis syndrome or use of pump inhibitors.
• 10% of polyps are adenomatous, more common in men.
• 30% of polyps are malignant.
• Solitary polyps are less than 2 cm and usually in the antral region.

Gastric Cancer (Adenocarcinoma)

• Most frequent malignant tumor in the stomach.
• Intestinal type presents as large masses that can penetrate and appear exofitic or ulcerated.
• Diffuse type is infiltrative and thickened, with signet ring cells.
• Most cases originate in the antrum and lesser curvature.
• Common symptoms include dyspepsia, dysphagia, weight loss, anorexia, early satiety, anemia, and hemorrhage.

Gastric Cancer (Metastasis and Other Risk Factors)

• Sites of metastasis are common: periumbilical, left axillary, ovaric, and Douglas Pouch.
• Gastric cancer arises in areas with low socioeconomic status and H. pylori infections are prevalent factors driving their origin.
• There are no significant differences in incidence in people with ulcers and those without.

Gastric Carcinoma

• Loss of CDH1 cadherin (up to 50% of cases) or loss of APC function.
• Increased Wnt signaling or gain-of-function in B-catenin expression, TGF-B signaling, BAX regulation of apoptosis or CDKN2 cell cycle control may play a role.
• Proinflammatory IL-1β and IL-1 can increase risk.
• Apical mucin vacuoles, desmoplastic reaction, subtotal gastrectomy can be involved in the development of disease.
• Advanced gastric cancer present in less than 20% of cases.

Gastric Lymphoma

• Histology or microscopic description of a section of gastric tissue, taken from biopsy analysis, is observed.

Peptic Ulcer Disease

• Gastric ulceration in the duodenum or stomach, primarily due to H. pylori infection, NSAIDs, or smoking.
• Gastric antrum and duodenum show increased acid secretion and decreased bicarbonate secretion.
• Gastric fundus or body exhibit modest acid secretion and associated atrophy that protects the duodenum and antrum, from developing ulcers.
• Ectopic gastric mucosa in parts of the intestines may also lead to ulcers.

Peptic Ulcer Disease: Risk Factors

• Risk factors for peptic ulcer disease include:
  • H. pylori: Infection with this bacteria is a main factor.
  • Smoking
  • Chronic obstructive pulmonary disease (COPD): a lung disease.
  • Hard drugs or cocaine: often lead to peptic ulcers.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs): Often cause stomach upset.
  • Alcohol cirrhosis, particularly in the duodenal region.

Hypertrophic Gastropathies

• Uncommon diseases characterized by giant cerebriform enlargement of rugal folds (epithelial hyperplasia).
• Does not involve inflammation.
• Two main types include Menetrier disease (in adults) and Zollinger-Ellison syndrome.

Zollinger-Ellison Syndrome

• Gastrin-secreting neuroendocrine tumors (gastrinomas) primarily appear in the small intestine or pancreas, although typically presenting as solitary lesions in 75% cases.
• Can be related to MEN Type 1 syndrome.
• Duodenal ulcers or chronic diarrhea can be present.
• Parietal cell hyperplasia is characteristic, often leading to excessive oxyntic mucosa in the stomach.

Bibliography

• This section contains information from the listed publications.