Met: PBL 2 (Cholera and Diarrhoea)

Question 1

What are oral rehydration solutions (ORS)?

Answer 1

Fluid replacement used to prevent or treat dehydration and involves drinking water with modest amounts of sugar and salt

Question 2

What is Ebola?

Answer 2

Viral haemorrhagic fever illustrating sore throat, muscular pain, headaches followed by vomiting, diarrhoea and rash then there is decreased function of liver and kidneys and some begin to bleed internally and externally

Question 3

What is cholera?

Answer 3

Infectious and often fatal bacterial disease of the small intestine, typically contracted from infected water supplies –> severe vomiting and diarrhoea

Question 4

What is a toxin?

Answer 4

A poison which acts as an antigen in the body

Question 5

Describe the structure of cholera toxin

Answer 5

Has 5 beta subunits and 1 alpha subunit (contains A1 and A2 parts) connected by a disulfide bridge

Question 6

Describe the mechanism of action of the cholera toxin on the small intestine

Answer 6

B subunit binds GM1 on luminal surface of enterocyte –> entire toxin is endocytosed –> A1 chain is released by reduction of the disulphide bridge –> A1 chain migrates to Golgi apparatus to be modified –> now free to bind with G protein for longer than normal (prolonged activation) –> G-protein binding activates adenyl cyclise –> cAMP –> over activates cytosolic PKA –> phosphorylation of CFTR chloride channels –> Cl- ATP mediated efflux –> Osmotic gradient –> Water, Na+, K+ and HCO3- then follow into gut lumen and there are diminished Na+ receptors to allow back into cell

Question 7

Describe the process of normal absorption in the gut

Answer 7

Glucose and sodium symport from lumen into enterocyte (down gradient)–> sodium pumped out simultaneously by 3Na+/2K+ ATPase pump to ensure gradient maintained –> GLUT2 on base lateral membrane allows glucose to pass out and into capillary –> water flows into blood stream due to created osmotic gradient

Question 8

What is the role of H+/Na+ exchanger proteins on the apical surface of enterocytes?

Answer 8

Pump sodium into cell and protons out –> production of carbonic acid in lumen –> dissociates to water and CO2 – CO2 diffuses into enterocyte –> dissociates to bicarbonate ions once more –> bicarbonate ions are reabsorbed by capillaries and carried away

Question 9

What are the two different functions of enterocytes?

Answer 9

Absorption and secretion

Question 10

Describe how enterocytes act as secretory cells

Answer 10

CFTR receptor (chloride) at apical surface can actively transport Cl- into lumen, passive transport of sodium at base lateral membrane back into the cell so more can be transported out into the lumen and there is a Na+/2Cl-/K+ protein pump on the basolateral surface which allows more chloride into the cell and out of the apical surface –> water follows causing a watery mucus lining of the epithelia to protect the surface

Question 11

Where are bicarbonate ions absorbed in the intestines?

Answer 11

Jejunum; and it’s absorption stimulates the absorption of sodium and water

Question 12

How may diarrhoea lead to an acid-base disturbance?

Answer 12

Watery diarrhoea can cause an increased loss of bicarbonate ions as well as potassium and this can lead to a base-deficit acidosis (metabolic acidosis)

Question 13

Why is bicarbonate actively secreted into the lumen of the ileum and colon?

Answer 13

Bacteria in this region produce fatty acids which decrease the pH (acidic), so bicarbonate is pumped out in exchange for chloride to combat the pH change

Question 14

What are the 6 different sources of fluid to the bowel?

Answer 14

Wtater from diet (mostly), saliva, gastric juice, bile, pancreatic juice, intestinal secretions

Question 15

What percentage of fluid to the bowel is reabsorbed?

Answer 15

98%

Question 16

Approximately, how many litres enters the colon per day, and how much is excreted?

Answer 16

1.5L enters, 100mls excreted

Question 17

What are the 3 different types of diarrhoea?

Answer 17

Secretory, osmotic, inflammatory

Question 18

Define diarrhoea

Answer 18

Passing foetal matter in quantities greater than 250g per day with notably greater fluidity and/or frequency

Question 19

Give 4 reasons as to why water is required in the lumen of the small intestine

Answer 19

To facilitate hydrolysis, to make mucus, to facilitate absorption and aid peristalsis

Question 20

Where exactly is the CFTR channel (affected by cholera) located in the small intestine?

Answer 20

At the apical surface of the epithelial cells of the small intestine (enterocytes) lining the crypts of Lieberkuhn

Question 21

How does the activation of CFTR channels in the small intestine lead to secretory diarrhoea?

Answer 21

Causes excess sodium to be secreted from the epithelium into the lumen of the intestine, and this causes sodium ions to follow passively via paracellular routes (between cells) and this increases the presence of NaCl in the lumen, increasing the osmotic gradient so that water follows, meaning there is greater production and secretion of fluid into the gut –> secretory diarrhoea

Question 22

Define paracellular transport

Answer 22

Transport of substances between cells

Question 23

Define transcellular transport

Answer 23

Transport of molecules through a cell (in through one surface and out through the other)

Question 24

Describe secretory diarrhoea

Answer 24

When there is an increase in active secretion, or there is an inhibition of absorption of fluid in the small intestine

Question 25

Describe osmotic diarrhoea

Answer 25

This occurs when too much water is drawn into the bowels due to an increased osmotic gradient - excessive sugar or salt consumption can therefore cause this type of diarrhoea, or alternatively, it can occur due to maldigestion, as seen in coeliac disease, where nutrients are left in the gut lumen, and therefore these can pull in more water

Question 26

Describe inflammatory diarrhoea

Answer 26

Occurs when there is damage to the mucosal lining which leads to passive loss of protein-rich fluids and a decreased abilit to absorb these lost fluids

Question 27

What is hypovolemia?

Answer 27

Loss of blood volume

Question 28

Describe the function of the SGLT1 protein in the small intestine

Answer 28

Symporter protein that transports two Na+ molecules and one glucose molecule across the apical surface of enterocytes

Question 29

What transporter proteins does cholera toxin affect?

Answer 29

Over-activates CFTR (Chloride ion efflux), affects receptors allowing the passive diffusion of sodium back through the apical surface and also increases passive transport of potassium, sodium, water and bicarbonate out of the cell

Question 30

Why is glucose required in oral rehydration solutions generally, and for the treatment of cholera?

Answer 30

Generally - allows intestinal sodium to be absorbed; via the symport transporter (SGLT1) so water moves into epithelial cells
In cholera - CFTR channel is over expressed and sodium and chloride transport is hindered, but the toxin has no effect on the SGLT1 protein so this allows sodium to be reabsorbed from the lumen to increase water uptake

Question 31

Why are intracellular sodium levels in the small intestine always quite low and constant?

Answer 31

The 3Na+/2K+ ATPase pump on the basolateral membrane pumps the sodium out into the extracellular fluid in order to ensure there is a maintained gradient for the diffusion of sodium into the enterocytes (potassium diffuses out into the ECF passively)