Gastric acid secretion: Disorders

Question 1

What is a peptic ulcer?

Answer 1

An ulcer in the digestive tract (oesophagus, stomach or duodenum)

Question 2

How do peptic ulcers form?

Answer 2

• Breakage of mucosal barrier - Imbalance b/w protective and damaging factors
• Exposure of tissues to the erosive effect of HCl and pepsin
• Affects oesophagus, stomach and duodenum

Question 3

What factors can predispose an individual to peptic ulceration?

Answer 3

• Gastric and duodenal infection with H.pylori is a major risk factor
  
  • H. pylori - Acquired in childhood
  • Environmental and host factors can determine the distribution and colonisation of H.pylori in the stomach
• Presence of a duodenal ulcer means there’s an 80% chance that individual has a H.pylori infection
• Increased acid secretion, increased pepsin secretion
• Use of NSAIDs, inhibit prostaglandins from providing protective effect, impaired mucosal defence

Question 4

Describe the protective factors that prevent autodigestion of the stomach

Answer 4

• Mucus layer - Protects gastric mucosa from low pH of gastric juice
• Secretion of alkaline mucus and HCO3-
• Protein in food acts as buffer
• Seamless epithelium with tigh junctions prevent back diffusion of H+ ions
• Replacement of damaged cells within the gastric pits (crypt cells)
• Prostaglandins (E and I) - Inhibit acid secretion, enhance blood flow
  
  • Mucosal blood flow removes excess acid that has diffused across the epithelial layer
  • Maintenance of mucosal integrity and reapir: growth factors (e.g., epidermal growth factor, insulin-like growth factor I)
• Peristalsis and fluid movement
• IgA secretion at mucosal surfaces
• Peyer’s patches (these are lymphoid tissues)

Question 5

How can prolonged NSAID use lead to gastric acid secretion disorders?

Answer 5

• NSAIDs (e.g. aspirin) block the synthesis of prostaglandings and TXA2 (thromboxane).
• Prostaglandins bind to mucus secreting cells, promoting them to secrete mucus, meaning there’s no longer as much mucus protecting the stomach from erosion due to HCl or pepsin.
• Prostaglandins prevent the binding of histamine to H2 receptors on parietal cells, thereby inhibiting acid secretion
• They also increase HCO3- secretion
• Prostaglandins are potent vasodilators, so decreased synthesis of them deceases mucosal blood flow
• NSAIDs also interfere with the repair of superficial injury, inhibiting platelet aggregation, they interfere with haemostasis processes
• The presence of acid in the stomach promotes NSAID-mediated gastric disorder

Question 6

How does H.pylori lead to peptic ulcers?

Answer 6

• H.- .pylori is gram negative, spiral shaped (can be coccoid) and aerobic
• Flagella enable its ‘corkscrew’ motility towards the gut epithelium

• It penetrates gastric mucosa (they’re able to survive under harsh conditions of the stomach)
• Highly pathogenic, many virulence factors:
  
  • Motility - Moves closer to eithelium (pH 7) via ‘corkscrew activity’
  • Mucinase activity - Digests protective mucus layer
  • Produces urease (converts urea to ammonia, which buffers luminal gastric acid and produces CO2 - diagonsitc use)
  • Cytotoxin-associated antigen (CagA) - Inserts pathogenicity islands and confers ulcer-forming potential
  • Vacuolating toxin A (VacA) - alters the trafficking of intracellular protein in gastric cells
    
    • Large number of outer membrane proteins: Adhesins (BabA), phosopholipases, and falgellum-associated proteins
• These virulence factors enable H.pylori attach and colonise gastric epithelium, they dysregulate gastrin secretion, causing it to be secreted more meaning more HCl is produced, hence leading to erosion and ulceration.

Question 7

Where and when are peptic ulcers common?

Answer 7

• Duodenal cap: first part of the duodenal cap
• Stomach: junction of antrum and body
• Distal oesophagus, especially in Barrett’s oesophagus
• Meckel’s diverticulum - An abnormal pouch in intestine that’s present from birth
• After gastroenterostomy to treat gastric outlet obstruction (weight loss, recurrent pains, ulcers)

Question 8

How are peptic ulcers investigated?

Answer 8

Diagnostic tests:

• Low dose PPI (omeprazole)
• Endoscopy (oesophagogastroduodenoscopy, EGD) - BEST way to investigate peptic ulcers
• Histological examination and staining of an EGD

Testing for H.pylori presence:

• Stool antigen test
• Evaluate urease activity with urea breath test

Question 9

Describe chronic peptic ulcers

Answer 9

• Occurs in upper GIT (pepsin and HCl)
• Asymptomatic in >80% people
• Low incidence in young; common in over 50s
• 90% incidene in developing countries
• Inflammation plays key role in disease process

Question 10

Describe acute peptide ulcer

Answer 10

Less frequent

• Develops from areas of corrosive gastritis (oesophagus, stomach, proximal duodenum), severe stress or shock (burns, trauma)
• Acute hypoxia of surface epithelium (i.e. ischaemia of gastric mucosa)

Outcomes:

• Severe bleeding
• Heal w/o scarring
• Chronic peptic ulcer

Question 11

What are the complications of peptic ulcers?

Answer 11

• GI bleeding (haemorrhage) - Most common complication
• Perforation (peritonitis) and penetration (liver and pancreas can be affected); leakage of luminal contents
• Narrowing of pyloric canal (stricture causing acquired pyloric stenosis in stomach) or oesophageal stricutre
• Malignat change 3-6 times more likely with H.pylori infection

Question 12

Describe the action of H2 receptor antagonists

Answer 12

E.g. cimetidine, Famotidine, nizartidine

Used to treat:

• Peptic ulcer
• Reflex oesophagitis

Mechanism of action:

• Inhibit histamine binding to H2 receptors on parietal cells
• Reduce gastric acid secretion, consequently reducing pepsin secretion. This is because for pepsinogen to be converted into pepsin, an acidic environement is needed
• Inhibit histamine, Ach and gastrin-stimulated acid secretion
• Can decrease basal and food-stimulated acid secretion by 90%

Clnical trials on H2 receptor antagonists:

• Promote healing of duodenal ulcers
• Relapse occurs if treatment stopped

Question 13

What are the side effects of H2 receptor antagonists and citemidine specfically?

Answer 13

Generally rare:

• Diarrhoea
• Muscle cramps
• Transient rashes
• Hypergastrinaemia

Cimetidine:

• Gynaecomastia in men (decreased sexual function, though this is rare)
• Cimetidine inhibits P450 enzymes → Decreased metabolism of number of drugs metabolised by P450 enzymes, e.g. anticoagulants, tricyclic antidepressants

Question 14

Describe the action of proton pump inhibitors and its side effects

Answer 14

E.g. omeprazole, lanzoprazole, pantoprazole, rabeprazole

Clinical uses:

• Peptic ulcer, reflux oesophagitis; as a component of therapy for H.pylori
• Can also be used in treatment of Zollinger-Ellison syndrome
• Drugs of choice, especially if hyper-secretion occurs (e.g. Zollinger-Ellison syndrome)

Mechanism of action:

• Weak bases; inactive at neural pH and irreversibly inhibit the H+/K+ ATPase pump
• Decreases basal and food-stimulated gastric acid secretion

Side effects:

• Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia; dizziness

Question 15

How is a H.pylori infection treated?

Answer 15

Combination therapy:

• Omeprazole, amoxicillin and metronidazole
• Omeprazole, clarythromycin and amoxicillin or tetracycline, metronidazole and bismuth chelates
• Lansoprazole, clarithromycin, tinidazole and bismuth chelates

Patient advice:

• Adhere to treatment
• Resistance to metronidazole
• Disulfiram-like reaction results if metronidazole taken with alcohol
  
  • Patient will feel severely ill, may stop taking medicine
  • Disulfiram inhibits acetaldehyde dehydrogenase, causes accumulation of acetaldehyde → unpleasant flushing and nausea, headache
• Do not give metronidazole first trimester
  
  • Development failure reported in 80s in infants whose mothers took this drug

Question 16

What are drugs that protect the gastric mucosa and how do they work?

Answer 16

E.g. bismuth chelate (colloidal bismuth subcitrate, tripotassium dicitratobismuthate), prostanoids. These have cytoprotective effects:

• Provide a physical barrier (coat) over the surface/base of the ulcer
• Enhances local synthesis of prostaglandins
• Promote bicarbonate secretion
• Bismuth chelate has toxic effects on the bacillus: it prevents the adherence of H.pylori to the mucosa or inhibit its proteolytic activity; stimulates bicarbonate secretion; increases prostaglandin synthesis; adsorbs pepsin

Misoprostal (synthetic analogue of PGE1) mode of action:

• Inhibits basal and food-stimulated gastric acid secretion
• Inhibits histamine, and caffeine-induced gastric acid secretion
• Increases mucosal blood flow
• Improves the secretion of HCO3- and mucus

Question 17

What are side effects of bismuth chelate?

Answer 17

• Nausea
• Vomiting
• Blackening of tongue and faeces