PEPTIC ULCER DISEASE AND GERD

• Peptic ulcer disease


  Disorders of the upper GI tract caused by the action of hydrochloric acid and pepsin, characterized by injury to the mucosa of the stomach, duodenum, or esophagus

  
• Peptic ulcers


  • Can be acute and chronic, and superficial or deep
  • Superficial defects of the GIT lining that involve mucosa, but do not affect the submucosal layer are called erosions
  • Deeper defects of the GIT lining are called ulcers
  • Penetrating ulcers may damage the blood vessels, causing hemorrhage, or may perforate the wall of the stomach
• Localization of peptic ulcers in GIT

  • Most frequent site is in the duodenum, within a few centimeters of the pylorus
  • Ulcers may also occur along the lesser curvature of the antral part of the stomach
  • More rarely, ulcers may be found in the lower end of the esophagus
  • Marginal ulcers of the stomach can be found in patients that had a surgical operation of the gastrojejunostomy

  
• Mucosal diffusion barrier


  • Mucus
  • Bicarbonates
  • Mucosal lining itself

  
• Mucus secretion


  1. Mucous cells in the neck of the gastric gland secrete mucus, which is made of glycoproteins called mucins, phospholipids, and water

  2. Secretion of mucus is increased upon vagal stimulation, and upon irritation of the stomach, e.g. ingestion of aspirin or alcohol

  3. Mucus forms a gel layer that separates the acidic content of the gastric lumen from the bicarbonate-rich fluid on the surface of mucosal cells

  4. It forms a physical barrier that slows diffusion of the acid and pepsin to the mucosal cell surface

  
• Bicarbonate secretion


  1. Mucous cells in the gastric gland also secrete bicarbonates

  2. Bicarbonates accumulate in the fluid that covers the surface of the mucosal cells, just underneath the mucus

  3. Bicarbonates form a chemical barrier that protects mucosal cells from the acid

  4. Bicarbonates act as a buffer that neutralizes H+ ions, thus preventing their destructive effect on the mucosal cells

  5. As bicarbonates neutralize the acid, pepsin becomes inactive and cannot damage the mucosal cells

  
• Neither the thick luminal membrane of the mucosal cells nor the intercellular clefts (equipped with tight junctions) are permeable to acid

  
• The entire mucosal lining is replaced every three days, so even if the mucosal cells were affected by the acid and pepsin, the induced structural derangements may not progress to the serious damage, because the affected cells are rapidly replaced with the new ones

  
• Pathogenesis of peptic ulcers

  Once H+ penetrates to deeper layers of the wall of the stomach, it produces two effects:

  1. H+ stimulates conversion of pepsinogen to pepsin, which causes further destruction of mucosa.

  2. H+ stimulates release of histamine, which then stimulates acid secretion, production of pepsinogen, and increases blood flow and capillary permeability. Gastric mucosa becomes inflamed and edematous.

  
• When the mucous barrier is damaged

  Gastric acid and pepsin can penetrate into the submucosal layer, and stimulate the mast cells to release histamine

  Histamine promotes gastric acid secretion by the parietal cells, forming a positive feedback mechanism

  
• Histamine


  Also causes inflammation of the gastric mucosa, by inducing vasodilation and increasing capillary permeability
• Causes of peptic ulcer disease

  • Precipitating factors:

  1. Helicobacter pylori (causes 80% of all peptic ulcers)

  2. Non-steroid anti-inflammatory drugs, e.g. aspirin (cause 20% of all peptic ulcers)

  Facilitating factors:

  1. Stressful lifestyle

  2. Irritating diet (spicy foods, alcohol, caffeine)

  3. Smoking

  4. Genetics
• How Helicobacter pylori survives in acidic environment


  It has flagella, which allow it to escape from the gastric lumen, and to take up residence under the layer of alkaline mucus.

  2. It preferentially settles in the antrum of the stomach, which contains no parietal cells that secrete acid.

  3. It produces an enzyme urease, which splits urea into ammonia and CO2. Ammonia serves as a buffer that neutralizes gastric acid locally in the vicinity of the H. pylori.

  
• Helicobacter pylori also produces catalase, an enzyme that protects the microbe from phagocytosis by neutrophils
• Ammonia produced by H.pylori damages the protective mucous layer of the stomach, making it thinner

  
• Once H. pylori has reached the gastric mucosal cells, it produces several adhesion proteins that allow the microbe to attach itself to mucosal cells, or to lodge in between the cells

  
• H. pylori secretes toxins that cause a persistent inflammation of the gastric mucosa (chronic gastritis)

  
• This impairs structural integrity of the mucosal cells, making them permeable for gastric acid

  
• Overall, the mucosal lining becomes extremely leaky, and loses its protective properties
• How NSAIDs cause peptic ulcers

  Chronic use of NSAIDs suppresses prostaglandin synthesis in GIT mucosa

  Prostaglandin E2 normally inhibits secretion of gastric acid, and increase secretion of bicarbonates and mucin

  Hence inhibition of prostaglandin secretion by NSAIDs causes the opposite - secretion of gastric acid is increased, and secretion of bicarbonates and mucin (that normally protect mucosa) is reduced

  These changes promote the development of peptic ulcer

  
• NSAIDs (e.g. aspirin) act by inhibiting enzyme cyclo-oxygenase, which blocks synthesis of prostaglandins
• Stressful lifestyle - glucocorticoids released during stress can also impair the protective mechanisms of the gastric mucosa

  
• Helicobacter pylori


  Secretes toxins that cause a persistent inflammation of the gastric mucosa (chronic gastritis)

  
• Helicobacter pylori


  • Impairs structural integrity of the mucosal cells, making them permeable for gastric acid
  • Overall, the mucosal lining becomes extremely leaky, and loses its protective properties

  
• NSAIDs


  Chronic use suppresses prostaglandin synthesis in GIT mucosa
• Prostaglandin E2


  Normally inhibits secretion of gastric acid, and increase secretion of bicarbonates and mucin

  
• Inhibition of prostaglandin secretion by NSAIDs

  Causes secretion of gastric acid to increase, and secretion of bicarbonates and mucin (that normally protect mucosa) to reduce

  
• These changes


  Promote the development of peptic ulcer

  
• NSAIDs (e.g. aspirin)


  Act by inhibiting enzyme cyclo-oxygenase, which blocks synthesis of prostaglandins
• Facilitating factors for peptic ulcer

  • Stressful lifestyle - glucocorticoids released from adrenal cortex in response to stress stimulate gastric acid secretion and reduce gastric mucosal defenses
  • Smoking - the incidence of the peptic ulcer disease is twice as high in smokers compared to non-smokers
  • Heredity - certain patterns of gastrin release and pepsin secretion can be determined by genetic factors. There are families with increased incidence of the peptic ulcer disease

  
• Clinical manifestations of peptic ulcer disease

  • Epigastric burning pain that is relieved by the intake of food (especially diary products) or antacids
  • Nausea
  • Abdominal upset (dyspepsia)
  • Significant proportion of ulcers is asymptomatic

  
• Epigastric pain in peptic ulcer disease

  • Pain of gastric ulcers typically occurs on an empty stomach
  • Pain of duodenal ulcer occurs 30 min to 2-3 hours after eating, may occur in the middle of the night, and disappear by morning
  • Epigastric pain results from sensorineural stimulation by gastric acid, or muscle spasm, or both
  • "Pain-food-relief" pattern

  
• Complications of peptic ulcer

  • GIT hemorrhage resulting from the damage of blood vessels in the submucosal layer caused by gastric acid and pepsin
  • Perforation of the stomach wall, resulting in the leak of the gastric content into the abdominal cavity

  
• Characteristics of patients with gastric vs. duodenal ulcers

  • Gastric ulcers - Primarily localized in the antral region of the stomach, Pathogenesis is related to weak mucous barrier that normally protects the mucosal cells from damage by the hydrochloric acid, Surprisingly, gastric acid secretion may be normal or even less than normal
  • Duodenal ulcers - More common than gastric ulcers, Pathogenesis is related to increased secretion of gastric acid and pepsin, Weak protective mucus barrier is another contributing factor, H. pylori reduces secretion of somatostatin by D-cells in the gastric antrum, which increases secretion of gastrin and gastric acid

  
• Somatostatin inhibits secretion of gastrin


  When lesser somatostatin is produced due to effects of H. pylori, secretion of gastrin is increased, which stimulates acid secretion by the parietal cells

  
• Patients with duodenal ulcers present with high serum levels of gastrin, as well as high gastric acid secretion (both basal and stimulated)

  
• Zollinger-Elison syndrome


  • Associated with increased secretion of gastrin, a hormone that increases gastric acid secretion by stimulating the parietal cells in stomach
  • Gastrin is secreted by gastrinoma, a neuroendocrine tumor of the pancreas or duodenum
  • Causes gastric and duodenal ulcers, as well as gastroesophageal reflux
  • Gastric acid inactivates pancreatic lipase secreted into the duodenum, resulting in steatorrhea

  
• Zollinger-Elison syndrome


  • Clinical manifestations include abdominal pain, diarrhea, and steatorrhea
  • Diagnosis is aided by measuring plasma gastrin levels

  
• Diagnosis of peptic ulcer disease

  • Barium contrast radiography
  • Endoscopy - During endoscopy, a biopsy can be taken for histology in order to exclude malignancy

  
• Endoscopy reveals association of Helicobacter pylori with gastric mucosa