Regulation and Disorders of Gastric Secretion

Question 1

Describe the stomach (anatomically), and what each part of it secretes.

Answer 1

It is made up of a fundus, body, antrum, and pylorus.

1. FUNDUS (thin walled upper portion): has glands that secrete pepsinogen, mucus, and HCL.
2. CARDIAC-AREA: mucus-secreting [the cardiac area of the stomach is where the contents of the oesophagus enter the stomach].
3. PYLORIC-AREA: mucus-secreting.
4. BODY (thin walled upper portion): contains chief cells (pepsinogen-secreting) and parietal cells (intrinsic factor-secreting).
5. ANTRUM (thick-walled lower portion): secretes mucus, pepsinogen and gastrin (Gastrin is important for contraction and secretion of acid).

Enterochromaffin-like cells (ECL) are a type of neuroendocrine cells found in the vicinity of parietal cells which secrete paracrine agents such as histamine that aids in the production of gastric acid.

Question 2

What are the contents of gastric juice (in the fasting state)?

Answer 2

• Cations: Na^+, K⁺, Mg²⁺, H⁺.
• Anions: Cl^-, HPO₄2⁺, SO₄^2-.
• Pepsinogen: (pepsinogen gets converted to pepsin. It is useful for the digestion of proteins).
• Lipase: (for digestion of triglycerides to fatty acids and glycerol).
• Mucus: (for protection).
• Intrinsic factor: (very important for B12 absorption).
• pH ~ 3.0

Question 3

How is gastric acid made in the stomach lumen?

Answer 3

1. CO₂ diffuses into the cell and combines with H₂O to form carbonic acid (H₂CO₃) under the influence of carbonic anhydrase.
2. H₂CO₃ can dissociate to form HCO₃^- and H⁺.
3. HCO₃^- is exchanged for Cl^- in the blood (chloride shift), decreasing the acidity of the venous blood from the stomach compared to the blood serving it.
4. The H⁺ forms H₂O and the cycle goes on. The H⁺ also has the capacity to be pumped into the stomach lumen (this process needs ATP) and gets exchanged for K⁺ via the K⁺/H⁺ ATPase pump.
5. There is a build up of Cl^- in the cell and it is able to come out through the chloride channel.
6. The net effect is the net flow of H⁺ and Cl^- out of the parietal cells and into the stomach lumen. This combines to form HCL.

Question 4

List some gastric secretions and their functions.

Answer 4

• MUCUS: alkaline, thick and sticky; increased HCO3-; forms a water-insoluble gel on epithelial surfaces, protecting against H+ secretion.
• RENNIN / CHYMOSINE: is a proteolytic enzyme related to pepsin that curdles milk into casein clots (particularly important in children).
• LIPASE: converts triglycerides into fatty acids and glycerol (if low lipase is produced lipids are not digested. This produces skid marks in toilet when pooping).
• INTRINSIC FACTOR: aids in the absorption of Vit B12, preventing pernicious anaemia.
• HCL: kills bacteria; acid denaturation of digested food; activates pepsinogen to pepsin (for protein digestion).

Question 5

What are the two different ways in which we can control HCl secretion?

Answer 5

HCl secretion is regulated by neuronal pathways and duodenal hormones.

• DIRECTLY: In the direct pathway, ACh, gastrin and histamine stimulate the parietal cell directly, triggering the secretion of H+ into the lumen.
• INDIRECTLY: In the indirect pathway, ACh and gastrin also stimulate the ECL cells, resulting in the secretion of histamine. Histamine then acts on the parietal cell.

Question 6

What are the three phases of gastric acid secretion?

Answer 6

1. Cephalic phase.
2. Gastric phase.
3. Intestinal phase.

Question 7

Describe acid secretion regulation during the cephalic phase.

Answer 7

• During the cephalic phase, smell, sight, taste, chewing, etc. stimulate ACh and gastric release.
• The cephalic phase stimuli activates the parasympathetic preganglionic neurones.
• These cause the enteric neurones can cause the release of HCL in three ways:-

1. It either release ACh that acts directly on the parietal cells, stimulating HCl secretion.
2. It can interact with the G cells to release gastrin. This gastrin can act on the ECL cells causing them to release histamine. The histamine binds to the perietal cells allowing them to secreate acid (HCL).
3. It can also directly act on the ECL cells (so they skip the G cell part).

Too much HCL secretion will stimulate the D cells which secrete somatostatin that has inhibitory effects on all the 3 cell types (parietal cells, ECL cells and G cells). This decreases the HCL secretion.

Question 8

Describe acid secretion regulation during the gastric phase.

Answer 8

• During the gastric phase, increased distention of the stomach increases peptide concentration, which increases the acidity of the stomach.
• The way this happens is :-
  
  • When the food has proteins in it, they act as a buffer that will remove the ability of HCL to stimulate the D cells. This means you can no longer inhibit acid secretion.
  • This then increases gastrin-mediated acid secretion.

It is not advisable to give people who have got problems with high acid secretion a high protein diet, as it makes the situation worse.

Question 9

Describe acid secretion regulation during the intestinal phase.

Answer 9

• During the intestinal phase, there is a balance of the secretory activity of the stomach and the digestive and absorptive capacities of the small intestine.
• The high acidity of the duodenal contents reflexly inhibits acid secretion (since the increased acidity would inhibit the activity of digestive enzymes, bicarbonate and bile salts).
• The distention of the duodenum, a hypertonic solution (indicating that the food has already been digested), amino acids, fatty acids, and monosaccharides all cause the release of enterogastrones [such as CCK (so you know lipids are present), secretin (if secretin is released the conditions are acidic so it releases bicarbonate)] which leads to the inhibition of acid secretion.
• Thus, the inhibition of acid secretion in the small intestine depends on:
  
  • The composition of the chyme.
  • The volume of the chyme.
  • Distention of duodenum.

Question 10

How is acid secretion inhibited during the intestinal phase?

Answer 10

• Short (within the ENS) and long (vagal) neuronal reflexes and hormones (enterogastrones, e.g. secretin, CCK and GIP) inhibit acid secretion by the parietal cells or gastrin secretion by the G cells, which is inhibited by somatostatin.
• Increased sympathetic discharge is inhibitory.
• Decreased parasympathetic discharge is stimulatory.
• Prostaglandin E2 is very important because it promotes bicarbonate and mucus secretion (it negatively regulates the hyperacidity of patietal cells).

Question 11

List some HCl secretion stimulants or factors that increase HCl secretion.

Answer 11

• Histamine.
• Acetylcholine.
• Gastrin.
• Caffeine.
• Alcohol.
• NSAIDs.
• Nicotine.
• Helicobacter Pylori.
• Zollinger-Ellison Syndrome.
• Hyperparathyroidism (over 8-30% of these people have got evelated acid secretion).
• Bile salts.
• Genetics.
• Stress.

Zollinger-Ellison Syndrome what is it? - It is a condition in which a gastrin-secreting tumour or hyperplasia of the islet cells in the pancreas causes overproduction of gastric acid, resulting in recurrent peptic ulcers.

Question 12

[HCl] can reach 150 mM. What does this depend on?

Answer 12

• Rate of secretion.
• Amount of buffering provided by the resting juice.
• Composition of the ingested food.
• Gastric motility.
• Rate of gastric emptying.
• Amount of diffusion back into the mucosa.

Question 13

In what ways is HCl essential for life?

Answer 13

• Defence (it can kill microbes).
• Protein digestion: activates pepsinogen to pepsin.
• Stimulates flow of bile and pancreatic juice (When there is a high acid concentration you secrete secretin. Secretin does not only promote bicarbonate secretion but it also has a bit of an effect on the contraction of the gallbladder).
• A lack of HCl causes the failure of protein digestion (achlorhydria or hypochlorhydria = when the production of gastric acid in the stomach is low or absent).

Question 14

What stimulates the secretion of pepsinogen?

Answer 14

• There are imputs to the chief cells from the nerve plexus.
• There are parallels between acid secretion and pepsinogen secretion.
• The stimulators/inhibitors of acid secretion during the cephalic and intestinal phases exert the same effect on pepsinogen secretion.

1. Pepsin is secreted by chief cells in the form of pepsinogen (zymogen).
2. It becomes activated if there is high acid concentration; the shape of the enzyme is altered by the high acidity which exposes its active site.
3. It is inactivated upon entry of food in the small intestine (HCO3- and peptides neutralise the H+).

Question 15

What is the point of pepsin secretion?

Answer 15

• It initiates the digestion of proteins by degrading food proteins into peptides.
• However, it is not required for food digestion.
• There are other enzymes that can digest proteins, such as trypsin, chymotrypsin and elastases.

Question 16

How do NSAIDs (e.g. aspirin) play a role in gastric acid secretion disorders?

Answer 16

• NSAIDs are acidic and cause the topical irritation of the gut.
• They impair the barrier properties of the mucosa by suppressing gastric prostaglandin synthesis.
• They also decrease gastric mucosal blood flow and inhibit platelet aggregation, both interfering with the repair of superficial injury.
• The presence of acid in the stomach promotes NSAID-mediated gastric disorders.
• It impairs the restitution (healing) process.
• It also inactivates FGF (fibroblast growth factor), which interferes with the haemostasis process.

Question 17

Describe the mechanism of peptic (gastric or duodenal) ulcer formation.

Answer 17

• The breakage of the mucosal barrier causes an imbalance between protective (such as mucus, bicarbonates) and damaging factors (such as the hyperacidity thats secreted there).
• This exposes the tissues to the erosive effects of HCl, bile acids and pepsin.
• 10% of the population is affected by ulcers.
• The sites where you’d be affected are the oesophagus, stomach and duodenum.

Question 18

List some symptoms of a peptic ulcer.

Answer 18

• Nausea.
• Dyspepsia (indigestion).
• Anorexia.
• Vomiting (blood).
• Epigastric pain.
• Chest discomfort.
• Weight loss.
• Black, tarry stools.
• Anaemia.

Question 19

Where/ under which circumstances are peptic ulcers more common?

Answer 19

• Duodenal cap (the first part of the duodenum as it is exposed to a lot of acidic chyme).
• The stomach (the junction of the antrum and the body).
• In the distal oesophagus, especially in Barrett’s oesophagus.
• In Meckel’s diverticulum (as the cells are thinner there).
• After a gastroenterostomy (as we affect how long before acidic products go without being neutralised).

Barrett’s oesophagus what is it? - It is a condition where the cells of the oesophagus (gullet) grow abnormally.

Meckel’s diverticulum what is it? - It is an abnormal pouch in the intestine that’s present from birth (true congenital).

Gastroenterostomy what is it? - It is the surgical creation of a connection between the stomach and the jejunum. The operation can sometimes be performed at the same time as a partial gastrectomy (the removal of part of the stomach). This is usually done either for the purpose of draining the contents of the stomach or to provide a bypass for the gastric contents.

Question 20

What are the causes of peptic ulcers?

Answer 20

• Hyperacidity is when there is a reflux of duodenal contents (oesophagus, stomach and duodenum).
• Presence of H. pylori is a risk factor for gastric cancer (if it is removed the risk is decreased). It is acquired in childhood (present in 10-15% of UK population). If you have duodenal ulcer, there is 80% chance that you have H. pylori infection.
• NSAIDs.
• Genetic factors.
• Sex – being male.

Question 21

List and describe the types of peptic ulcers.

Answer 21

1. CHRONIC peptic ulcers are common: -
   
   • Occurs in the upper GIT (pepsin and HCl).
   • Asymptomatic in >80% of people.
   • Low incidence in young people, more common in people over 50s.
   • 90% incidence in developing countries (as H. pylori is quiet common in thses areas).
   • Inflammation plays a key role in the disease process.
2. ACUTE peptic ulcers are less frequent: -
   
   • Develops from areas of corrosive gastritis (oesophagus, stomach, proximal duodenum), severe stress or shock (burns or trauma).
   • Acute hypoxia of the surface epithelium (i.e., ischaemia of the gastric mucosa) can cause acute peptic ulcers.

Question 22

List some factors that prevent the infection of the gastric mucosa.

Answer 22

• HCl, pepsin.
• Mucus production.
• Peristalsis and fluid movement.
• Seamless epithelium with tight junctions.
• Fast cell turnover.
• IgA secretion at mucosal surfaces.
• Peyer’s Patches - (they are small masses of lymphatic tissue found throughout the ileum region of the small intestine. Also known as aggregated lymphoid nodules, they form an important part of the immune system by monitoring intestinal bacteria populations and preventing the growth of pathogenic bacteria in the intestines).

Question 23

List some protective factors that prevent the autodigestion of the stomach.

Answer 23

• Secretion of alkaline mucus and HCO3-.
• Protein content of food.
• Presence of tight junctions between epithelial cells lining the stomach and fibrin coat.
• Replacement of damaged cells within the gastric pits.
• Prostaglandins (E and I): inhibit acid secretion and enhance blood flow.
• Mucus layer protects the gastric mucosa from the low pH.

Question 24

Describe H. Pylori.

Answer 24

• It is a gram-negative, spiral-shaped [can also be coccoid (round)] aerobic bacterium.
• It penetrates the gastric mucosa (it is able to survive the harsh conditions of the stomach).
• It is highly pathogenic, with many virulence factors.

Question 25

List some virulence factors of H. Pylori.

Answer 25

• Motility: flagella, moves close to the epithelium.
• Produces urease (which converts urea to ammonia, which buffers gastric acid and produces CO2).
• Cytotoxin-associated antigen (CagA): inserts pathogenicity islands and confers ulcer-forming potential; causes apoptosis of cells and affects tight junctions.
• Vacuolating toxin A (VacA): alters the trafficking of intracellular proteins in gastric cells. A large number of outer membrane proteins: Adhesins (BabA), phospholipases, porins, iron transporters, and flagellum-associated proteins.

H. Pylori is the commonest cause of peptic ulcer. It increases the peptic ulcer risk by 10-20%.

Question 26

Describe the mechanism of H. Pylori causing mucosal damage.

Answer 26

1. The H. Pylori bores its way through the mucosa using its corkscrew motility, and attaches to the epithelium using some of the virulence factors.
2. While there, it releases urease to convert urea to ammonia, which neutralises any acidity in the area, and stops it from being secreted.
3. Therefore, any bacteria can come and survive in the area.
4. The epithelium starts bleeding and being inflamed due to the HCl, pepsin and toxin exposure.

Question 27

A suspected ulcer must be investigated. What diagnostic tests can are done?

Answer 27

• An endoscopy (oesophagogastroduodenoscopy, EGD).
• Histological examination and staining of an EGD biopsy.

Question 28

How would you test for the presence of H. Pylori?

Answer 28

• Stool antigen test.
• Evaluate urease activity (with a marked carbon urea tablet).
• Urea breath test.

Question 29

What are some complications of peptic ulcers?

Answer 29

• Haemorrhage (GI bleeding).
• Perforation (peritonitis) and penetration (liver and pancreas may be affected); leakage of luminal contents.
• Narrowing of the pyloric canal (stricture causing acquired pyloric stenosis in the stomach) or oesophageal strictures.
• Malignant change becomes 3-6 times more likely with H. Pylori infection.