Regulations and Disorders of Gastric Acid Secretion

Question 1

What are the contents of gastric juice?

Answer 1

Contents of gastric juice (fasting state):
Cations- Na+, K+, Mg2+, H+
Anions- Cl-, HPO42+, SO42-
Pepsinogen (inactive and gets converted to pepsin in acidic conditions)
Lipase
Mucus
Intrinsic factor
pH ~3.0
Gastric juice adds ~2.5L/day to intestinal contents
Is it essential for digestion and absorption

Question 2

How are different parts of the stomach structured?

Answer 2

Thin-walled upper portion of the stomach (fundus and body)- mucus, HCl and pepsinogen
Thick-walled lower portion (antrum)- ↑gastrin secretion; gastrin mediates acid secretion (HCl secretion)
There are also exocrine secretion of the stomach- mucus, acid, pepsinogen
Enterochromaffin-like cells (ECL) -> paracrine agents e.g. histamine

Question 3

How is gastric acid made in the stomach?

Answer 3

CO2 can diffuse form the blood into the cell, it combines with water to form carbonic acid
Carbonic acid is dissociated into bicarbonate ions an protons
The protons combine with hydroxide ions to form water
This step is like a cycle because water then splits into OH- and H+ is used
Th bicarbonate ion is exchanged for chloride and the bicarbonate goes into the blood site done via active transport-called the chloride shift
Bicarbonate neutralises acid
HCO3- is exchanged for Cl- in the blood → ↓acidity of venous blood from stomach compared to blood serving it
Excess Cl- diffuses out into the stomach through chloride channels; K+/H+- ATPase H+ out into stomach lumen
Net effect- net flow of H+ and Cl+ (forming HCl) out of the parietal cell and into stomach lumen (Stomach secretes ~2L of HCl/day at 150mM)

Question 4

What are the different types of gastric secretions?

Answer 4

Technically some amount of gastric juice is described as resting juice (= plasma, but alkaline, pH 7.4-7.7; ↑HCO3-)
Mucus: alkaline, thick and sticky, forms water-insoluble gel on epithelial surface; ↑HCO3– protects against H+ secretion (as it neutralises it)
Rennin (chymosin): produced at birth; curdles milk intocasein clot; production replaced by pepsinogen as we get older
Lipase: triglycerides → fatty acids and glycerol
What will happen if you do not release lipase? You get steatorrhea
Intrinsic factor (prevents pernicious anaemia): absorption of vitamin B12
Gastric acid (HCl):
Kills bacteria; acid denaturation of digested food; creates the optimum pH for the activation of pepsinogen to pepsin for protein digestion
Promotes the action of gastric lipase; and the secretion of pancreatic HCO3-

Question 5

What is the difference between secretions from parietal and non-parietal cells?

Answer 5

Antrum has got G cells, next to G cells are the D cells

Non-parietal secretions contain resting juice = plasma; but alkaline, pH7.4; ↑HCO3-

Question 6

What are the phases to the secretion of gastric juice?

Answer 6

HCl secretion by parietal cells
There are phases to the secretion of gastric juice
At meal times, ↑ HCl secretion (see why later)
Phases involved:
-Cephalic phase
-Gastric phase
-Intestinal phase
HCl secretion is regulated by neuronal pathways and duodenal hormones
How do they do that?
Direct pathway, acting on parietal cells e.g. gastrin → ↑ acid secretion
Indirect pathway, influence the secretion of gastrin and histamine → ↑ acid secretion

Question 7

What happens during the cephalic phase of gastric acid secretion?

Answer 7

Cephalic phase (meal times- smell, sight, taste, chewing): ACh and gastric release
Cephalic phase stimulates the parasympathetic pathway which stimulates enteric neurons
ACh stimulates histamine release from ECL cells
ACh acts directly on parietal cells → HCl secretion
Gastrin stimulates histamine release from ECL cells
Gastrin acts directly on parietal cells → HCl secretion
When there is too much acid secretion that’s when the paracrine factor, somatostatin, comes in from D cells and inhibits everything

Question 8

What happens during the gastric phase of gastric acid secretion?

Answer 8

Gastric phase (distension of stomach; ↑ peptide concentration): ↑ acidity (↑[H+]) - important quantitatively because it is the gastric phase that produces the most HCl secretion
The distension will have an effect on the enteric NS because it will cause the vago-vagal reflex where Ach is released and we know that the presence of food in the stomach will also stimulate the G cells, particularly peptides
Too much HCl stimulates the D cells to release somatostatin
Acid secretion decreases as the acidity of the lumen increases
Can you explain why?* No
Peptides stimulate G cells

Question 9

How does protein content of a meal affect H+ secretion (during the gastric phase)?

Answer 9

Acidity of lumen of stomach is ↑ before a meal (no buffers)
More proteins → ↑ peptides in stomach (↑ gastrin secretion)
What do proteins do to luminal acidity?
Proteins act as buffers in the gastric lumen
And so what? HCl secretion increases
Mechanism explained:
H+ + proteins → ↓ [H +]; protein acts as a buffer; proteins remove the inhibitory powers of HCl on gastrin secretion and hence acid secretion
But…
This then increases gastrin-mediated acid secretion

Question 10

What happens during the intestinal phase of gastric acid secretion?

Answer 10

Intestinal phase: balances the secretory activity of the stomach and the digestive and absorptive capacities of small intestine
High acidity of duodenal contents reflexly inhibits acid secretion
Increased acidity inhibits the activity of digestive enzymes, bicarbonate and bile salts
Distension of duodenum, hypertonic solution, amino acids, fatty acids, monosaccharides all inhibit acid secretion
Thus, inhibition of acid secretion in the small
intestine depends on:
Composition of chyme
Volume of chyme
Distension of duodenum
Those factors can promote the release enterogastrones, released by cells within the duodenum
If it is fats CCK, if it is acidic secretin

Question 11

How is acid secretion inhibited during the intestinal phase?

Answer 11

Short and long 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 (stomach, intestine, delta cells of pancreas, hypothalamus, brainstem, hippocampus)
Certain characteristics of the chyme will trigger neuronal reflexes and that will inhibit the neural input in the brain which inhibits Ach mediated effects
There is also a stimulatory effect where enterogastrones are released

Question 12

What is the role of histamine, ACh and gastrin in gastric acid secretion?

Answer 12

Histamine, ACh, and gastrin binding to their receptors on parietal cells → ↑↑HCl secretion
PGE2 negatively regulates HCl secretion. What does that mean?

Question 13

How can acid secretion become elevated?

Answer 13

HCl secretion stimulants or factors that increase HCl secretion
Histamine
Acetylcholine
Gastrin
Caffeine*
Alcohol*
NSAIDs*
Nicotine*
Helicobacter pylori
Zollinger-Ellison syndrome acid secreting tumours
Hyperparathyroidism (8-30%)
Bile salts
Maybe genetic factors?
*Avoid these drugs if you have peptic ulcer

Question 14

Is HCl essential for life?

Answer 14

Note that the [HCl] can reach 150mM, depending on:
Rate of secretion
Amount of buffering provided by the resting juice
Composition of ingested food
Gastric motility
Rate of gastric emptying
Amount of diffusion back into mucosa
So it is essential for life:
Defence – kills germs
Protein digestion: activates pepsinogen to pepsin
Lack of HCl causes failure of protein digestion (achlorhydria or hypochlorhydria = production of gastric acid in the stomach is absent or low)
Stimulates flow of bile and pancreatic juice (HCO3–rich watery secretions)
Promotes the action of gastric lipase

Question 15

What stimulates the secretion of pepsinogen?

Answer 15

Inputs to chief cells from nerve plexus
There are parallels between gastric acid secretion and pepsinogen secretion
Stimulators/inhibitors of acid secretion during the cephalic and intestinal phases exert same effect on pepsinogen secretion

Secreted by chief cells in the form of pepsinogen (inactive, a zymogen)
Activated if [H+] is high; shape altered by high acidity which exposes its active site
-Autocatalytic feedback process
Inactivated upon entry of food in the small intestine (HCO3- and peptides neutralise the H+)

Question 16

What is the point of pepsin secretion?

Answer 16

Initiates digestion of proteins - degrades food proteins into peptides
But pepsin is not required for food digestion
Which other enzymes could digest proteins?
A required substance secreted by the parietal cells is intrinsic factor

Question 17

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

Answer 17

NSAIDs = acidic, cause topical irritation of gut
…impair the barrier properties of mucosa
…suppress gastric prostaglandin (PG) synthesis
…↓ gastric mucosal blood flow
…interfere with the repair of superficial injury
…inhibit platelet aggregation- because inhibits thromboxane(?)
Presence of acid in the stomach promotes NSAID-mediated gastric disorder
How?
Impairs restitution process
Inactivates FGF which interferes with the haemostasis process
Way forward = discover and develop stomach-sparing NSAIDs

Question 18

What protective factors prevent autodigestion of the stomach by HCl and pepsin?

Answer 18

Gastric juices: 150mM HCl & pepsin in the stomach
Mucus layer protects the gastric mucosa from the low pH
Secretion of alkaline mucus and HCO3-
Somatostatin inhibits gastrin release (negative feedback control)
Protein content of food
Epithelial cells remove excess H+ via membrane transport systems; tight junctions of epithelial cells prevent back diffusion of H+ ions
Prostaglandins (E and I): inhibit acid secretion and enhance blood flow
Mucosal blood flow removes excess acid that has diffused across the epithelial layer
Maintenance of mucosal integrity and repair: growth factors (e.g., epidermal growth factor, insulin-like growth factor I) and PGs
Replacement of damaged cells within the gastric pits

Question 19

What gastric acid secretion disorders can arise?

Answer 19

GIT function: storage, secretory, digestion, absorption of nutrients, salts, water, metabolism and elimination of (undigested) wastes
Malformation of GIT: ↓ nutrient status of the individual
Peptic ulcer and mechanism of peptic ulcer formation:
10% of population affected by ulcers
Sites affected: Oesophagus, stomach and duodenum
Breakage of mucosal barrier
…imbalance between protective and damaging factors of GIT
…exposure of tissues to the erosive effects of gastric acids (HCl, bile acids) and pepsin

Question 20

What are the factors responsible for gastric acid secretion?

Answer 20

Histamine
Acetylcholine
Gastrin
Food/protein, alcohol, smoking, caffeine, NSAIDs
Zollinger-Ellison syndrome
Hyperparathyroidism
Stress? - Can it aggravate it once ulcer is present?
Bile acids are irritants
Genetic?
Helicobacter pylori

Question 21

Where are peptic ulcers common?

Answer 21

Duodenal cap/ampulla: first part of the duodenum; smooth walled; dilated; mesenteric
The stomach – junction of antrum and body
Distal oesophagus, especially in Barrett’s oesophagus
Meckel’s diverticulum – outpouching or bulge in the small intestine (congenital)
Weight loss surgery (gastroenterostomy) weight loss

Question 22

What are the different causes and outcomes of peptic ulcers?

Answer 22

Causes of peptic ulcer -
Hyperacidity; reflux of duodenal contents (oesophagus, stomach and duodenum)
Presence of H. pylori is a risk factor for gastric cancer – eradication → ↓ risk
NSAIDs; Genetic factors; Sex – being male?
Outcome:
Complete healing and replacement of tissue and some scarring
Chronic peptic ulcer is common:
Occurs in upper GIT (pepsin and HCl)
Asymptomatic in >80% of people
Low incidence in young; common in over 50s
90% incidence in developing countries
Inflammation plays a key role in the disease process

Question 23

What are the types of peptic ulcers?

Answer 23

Acute peptic ulcer: less frequent
Develops from areas of corrosive gastritis (oesophagus, stomach, proximal duodenum), severe stress or shock (burns, trauma)
There are also acute hypoxia of surface epithelium (i.e., ischaemia of gastric mucosa)
Outcomes:
Severe bleeding
Heal with no scarring
Chronic peptic ulcer

Question 24

How are duodenal ulcers and H. pylori linked?

Answer 24

Gastric and duodenal infection with H. pylori is a major risk factor
H. pylori - acquired in childhood (present in 10-15% of UK population)
Environmental and host factors can determine the distribution and colonisation of H. pylori in the stomach
If you have duodenal ulcer, there is 80% chance that you have H. pylori infection

Question 25

What is H. pylori and how does it work?

Answer 25

H.Pylori (Campylobacter pyloridis) and peptic ulcer
Gram negative; spiral shaped (can be coccoid too) aerobic bacterium
Penetrates gastric mucosa (able to survive under the harsh condition of the stomach)
Highly pathogenic, with many virulence factors
Peptic ulcer = ulcer in the digestive tract (in the stomach or duodenum)
The flagella enables its ‘corkscrew’ motility towards the gut epithelium

Question 26

What are the virulence factors of H. pylori?

Answer 26

Motility: flagella; moves close to the epithelium (pH 7)
Produces urease (converts urea to ammonia, which buffers gastric acid and produces CO2)
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
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 – ↑peptic ulcer risk by 10-20%

Question 27

How does H. pylori affect the cells?

Answer 27

Flagella allows bacterial motility and chemotaxis to colonise under mucosa
Lipopolysaccharides allows it to adhere to host cells
Endotoxin for gastric mucosal injury
Secretory enzymes also for gastric mucosal injury
CagA causes remodelling of the host cell (actin specifically) and apoptosis inhibition which could end up with cancer
The virulence factors enable H. pylori attach and colonise the gastric epithelium
H. pylori infection dysregulates gastrin secretion → ↑gastrin secretion
H. pylori infection increases the number of G-cells?
H. pylori infection induces reduction of the number of antral D-cells?

Question 28

How can a peptic ulcer be investigated?

Answer 28

Diagnostic tests:
Endoscopy (oesophagogastroduodenoscopy, EGD)
Histological examination and staining of an EGD biopsy
Test for the presence of H. pylori
Stool antigen test
Evaluate urease activity
Urea breath test

Question 29

What are the complications of a peptic ulcer?

Answer 29

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