E2 The biology of dyspepsia

Question 1

state some symptoms of dyspepsia

Answer 1

• upper abdominal pain / discomfort
• heartburn
• gastric reflux
• nausea
• vomiting

Question 2

what are the problems of dyspepsia related to?

Answer 2

gastric acid

Question 3

why does reflux of stomach acid cause burning and pain?

Answer 3

• oesophagus has limited protection against gastric acid compared to the stomach lining
• excess acid can cause tissue damage due to lack of thick mucus layer

Question 4

what is the name for acid-secreting cells in the stomach and where are they localised?

Answer 4

• parietal cells
• localised in a specific region in the stomach (fundus, upper half)

Question 5

what is the majority of the stomach lined with?

Answer 5

• simple epithelium (a single layer of epithelial cells)
• these cells are called surface mucous cells
• they secrete a layer of mucus that protects the lining of the stomach against acid

Question 6

where are their sphincters in the GIT that stop gastric acid being where it shouldn’t? what is this concept called?

Answer 6

• 2 sphincters prevent excess acid in the intestine and oesophagus (lower oesophageal sphincter and pyloric sphincter)
• this allows for compartmentilisation

Question 7

what 2 adaptations does the stomach epithelium have for protection against acid?

Answer 7

• mucus
• tight junctions between cells

Question 8

describe and explain how mucus protects the gastric epithelium against gastric acid

Answer 8

mucous:
- glycosolated proteins form a thick, viscous, gel-like layer on surface of cells
- bicarbonate neutralises gastric acid

acid in the stomach does not easily mix with mucus

Question 9

describe and explain how tight junctions between mucous surface cells in the stomach help protect against gastric acid

Answer 9

• protein structures restrict movement of ions and water between cells (limits and regulates transport)
• prevents acid leaking through the epithelial layer
• prevents damage to underlying tissue

Question 10

tight junctions divide the cell membrane of the stomach into 2 compartments, what are they?

Answer 10

• apical (outside, towards the lumen)
• basolateral (inside, facing the basement membrane)

Question 11

compare and contrast the structure of the stomach epithelium and the oesophageal epithelium

Answer 11

stomach
- simple columnar epithelium
- mucous cells cover most of the internal surface

oesophagus
- non-keratinised stratified squamous epithelium
- specialised goblet cells secrete mucus but the mucus layer is much thinner than the stomach’s due to having fewer goblet cells

Question 12

compare and contrast the protection against gastric acid that the stomach and oesophagus epitheliums provide

Answer 12

stomach
- adequate protection against gastric acid

oesophagus
- less protection against gastric acid
- in people with GORD, tissues can be damaged or destroyed

Question 13

where are parietal cells located?

Answer 13

• in gastric pits
• there are about 100 gastric pits per square millimetre

Question 14

functions of gastric acid

Answer 14

• helps with the conversion of pepsinogen to pepsin (functional enzyme that breaks down protein)
• kills many types of bacteria

Question 15

state the structures of the gastric pits in the stomach

Answer 15

• mucus layer
• mucous cell
• parietal cell
• other cell types eg. G cells, chief cells
• connective tissue

Question 16

function of G cells

Answer 16

produce gastrin

Question 17

function of chief cells

Answer 17

produce pepsin

Question 18

what is acid secretion stimulated by?

Answer 18

extracellular signals:
- histamine
- acetylcholine
- gastrin (peptide hormone)

• these signals can activate parietal cells by interacting with receptors localised on the basolateral membrane

Question 19

why is a lot of gastric acid able to be secreted in the stomach?

Answer 19

there are lots of parietal cells next to each other in the gastric pits

Question 20

what does histamine bind to when stimulating gastric acid secretion?

Answer 20

H2 receptor

Question 21

what does ACh bind to when stimulating gastric acid secretion?

Answer 21

M3 receptor

Question 22

what does gastrin bind to when stimulating gastric acid secretion?

Answer 22

CCK2 receptor

Question 23

hydrochloric acid is secreted into the stomach through intermediate steps, what are they?

Answer 23

• uptake of carbon dioxide by diffusion
• hydration of carbon dioxide by carbonic anhydrase enzyme to produce proton and bicarbonate
• apical side is where H+ is exported by the gastric proton pump (orange circle) in exchange for K+
• basolateral side is where uptake of Cl- occurs in exchange for bicarbonate ions

Question 24

what transport mechanisms can be seen in this image of a parietal cell?

Answer 24

ion channels
solute transporters
uniporters
symporters
antiporters
ion pumps
diffusion

Question 25

what kind of receptor is a H2 receptors?

Answer 25

GPCR histamine binds to it at parietal cell basolateral side

Question 26

what is Pepcid?

Answer 26

- H2 receptor antagonist that can be prescribed - inhibits H2 receptor and prevents secretion of HCl

Question 27

where can famotidine bind and what does this binding cause?

Answer 27

- binds in the histamine binding pocket of the H2 receptor - if famotidine binds, it stops histamine binding and having an effect - inhibits acid secretion

Question 28

describe how H2 receptor antagonists can be used to treat dyspepsia

Answer 28

- prevent binding of histamine - the receptor then can't be activated by histamine - conformational change of protein leads to a different shape despite the antagonist binding in a similar location

Question 29

what happens at E1?

Answer 29

hydrogen ions being readily transported into the contents of the stomach

Question 30

what happens at E2?

Answer 30

where transport of potassium occurs

Question 31

describe more about this image such as what state is more common and what PPIs do to these configurations

Answer 31

- transition between these states continuously - PPIs lock proton pumps in the E2 configuration so it can't transport any hydrogen ions across the apical membrane

Question 32

what path do PPI drugs follow in the body for them to have an affect on gastric acid secretion?

Answer 32

stomach duodenum blood parietal cells

Question 33

describe the behaviour of PPI tablets in the stomach

Answer 33

- pH 1-2 - protected by enteric coating, remains as prodrug - doesn't target parietal cells at this stage, it bypasses them

Question 34

describe the behaviour of PPI tablets in the duodenum

Answer 34

- pH 6-6.5 - uncharged - easily absorbed

Question 35

describe the behaviour of PPI tablets in the blood

Answer 35

- pH 7.4 - uncharged - systemic circulation

Question 36

describe the behaviour of PPI tablets in the parietal cells

Answer 36

- pH ≤ 2 - ionised, forms active drug and reacts with target - targets parietal cells from basolateral side so need to go through systemic circulation to reach basolateral side - when activated, PPI limits proton transfer