Diarrhoea 1 - Anatomy and Pathophysiology

Question 1

Gastrointestinal Motility

Answer 1

• The GI tract is in a continuous contractile, absorptive, & secretory state
• Muscle, CNS, ENS (enteric nerve system), and humoral pathways control GI movement
• 4 phases to movement in the GI tract
– Peristalsis is most important, moves contents
through GI tract

Question 2

GI tracts own nervous system =

Answer 2

ENS (enteric nerve system)

Question 3

GI Motility

Answer 3

• increased transit time
- Increased water
absorption -> constipation

•decreased transit time
- Decreased water and nutrient absorption -> diarrhoea

Question 4

Diarrhoea:

A Failure of Fluid-Handling

Answer 4

In a “normal” adult small intestine:
• Intake of 9 litre/day
– diet 1.8 litre,
– endogenous secretions 7.2 litre
• Input of fluid into the colon: 1.5-2.0 litre/day
• Output of fluid in faeces: 100-200 ml/day.

Question 5

A major function of the colon is to

Answer 5

reabsorb fluid

Question 6

Two Major forms of Diarrhoea

Answer 6

• Osmotic diarrhoea

- Secretory Diarrhoea

Question 7

-Osmotic diarrhoea

Answer 7

Excess of osmotically active particles in the gut lumen
• Osmotic laxatives
• Excessive solutes in the lumen
• Inflammation within the mucosa (leads to malabsorption of electrolytes, leads to osmotic misbalance in GI tract)
• Motility disorders (if food moves to fast through GI tract and SI it will end up in colon without losing too many osmotic particles so will draw water back up into colon)

Question 8

-Secretory Diarrhoea

Answer 8

-more of an active process

Bowel mucosa secretes excess water into the lumen
• Cholera toxin
• Other infective causes
• Specific electrolyte transport defects (e.g. congenital chloride-losing diarrhoea)
so when things go wrong with transporters in gut wall then that can lead to secretory diarrhoea

Question 9

Osmotic Diarrhoea

-Excessive numbers of osmotically active particles can be present due to:

Answer 9

• Ingestion non-absorbable solutes e.g. osmotic laxatives
• Malabsorption of specific solutes e.g. glucose-galactose
malabsorption (don’t have the right glut transporters in gut so pass down gut unabsorbed and enter into colon and form osmotic gradient and draw water from surrounding body into colon)
• Damage to the mucosa resulting in less absorption e.g. acute viral gastroenteritis
• Motility disorders as seen in irritable bowel syndrome resulting in increased solutes reaching the colon.

Question 10

how to diagnose osmotic diarrhoea

Answer 10

-Removing source of osmotically active particles (e.g. by fasting) stops diarrhoea

Question 11

Secretory Diarrhoea

-Increased fluid secretion normally due to:

Answer 11

• Specific biological mechanisms involving pathogen- produced factors (e.g. cholera toxins)
• Inherent abnormalities in the enterocytes
-Fasting does not alter these mechanisms, and therefore does not halt diarrhoea

Question 12

diarrhoea can be associated with

Answer 12

• Can be associated with an infectious cause
– Shigella, Salmonella, E. Coli among most common
• Most diarrhoea is self-limiting
• Defined as an increase in stool frequency or water
content

Question 13

Prevalence of diarhoae

Answer 13

• Prevalence of diarrhoea varies in developed vs. non-developed countries
– 1.3 billion episodes/yr in developing countries -> 4 million deaths

Question 14

important agent in diarrhoea

Answer 14

infection

Question 15

(Some) Infective Agents Causing Diarrhoea

Answer 15

Viruses
Bacteria
Parasites

Question 16

(Some) Infective Agents Causing Diarrhoea - Viruses

Answer 16

• Rotavirus
• Norwalk virus
• Norovirus - winter sickness
• Calicivirus

Question 17

(Some) Infective Agents Causing Diarrhoea - bacteria

Answer 17

• Campylobacter jejuni
• Salmonella
• Escherichia coli
• Shigella
• Yersinia entercolitica
• Clostridium difficile

Question 18

(Some) Infective Agents Causing Diarrhoea - Parasites

Answer 18

• Cryptosporidium

- Giardia lamblia

Question 19

Cholera Toxin Mechanism of Action steps

Answer 19

can be a very major infection

a) The toxin B subunitsbinds to the membrane receptor, GM1, and the A subunit is inserted through the membrane.
b) The complex is endocytosed by the target cell.
c) Proton pumps acidify the CT-containing endocytic vesicle, causing the toxin subunits to dissociate.
d) The A1 subunit is an ADP-ribosyltransferase that cleaves NAD into adenosine diphosphoribose (ADPR) and nicotinamide and covalently bonds the former to the α subunit of the Gs adenylyl cyclase–stimulatory G protein.
e) The intrinsic GTPase activity of the α subunit isblocked, allowing GTP to remain bound to it; the Gsα-GTP complex activates adenylyl cyclase (AdCy).
f) Increased cAMP-production increases CFTR Chloride pump activity, & increases secretion of water into gut lumen

Question 20

cholera toxin is made up of

Answer 20

6 B subunits surrounding 1 A subunit

Question 21

Cholera Toxin Mechanism of Action - what do B subunits interact with

Answer 21

B subunits interact with host cells via GM1 receptor - high affinity

Question 22

(By way of a detour… The CFTR)

Answer 22

• CFTR = Cystic Fibrosis Transmembrane Conductance Regulator
• Protein mutated in cystic fibrosis
• The only ATPase “ion pump” that pumps ions downhill
- needs ATP to be hydrolysed

Question 23

Clostridium Difficile

Answer 23

•The major cause of diarrhoea and colitis in patients exposed to antibiotics (~20%). •Fecal - oral route of transmission

Question 24

Clostridium Difficile -

steps to infection

Answer 24

•Three steps to infection

• Alteration of normal colonic flora
• Colonic colonization of C. difficile
• Growth and production of toxins
• Infection can lead to formation of colitis and toxic megacolon

when the gut flora is depressed in patients - high possibility of C.Diff colonization in gut - produces toxin

Question 25

Clostridium Difficile

• Pharmacological Treatment

Answer 25

• Discontinue offending antibiotic
• Metronidazole (contraindicated in patients with liver or renal impairment)
• Vancomycin (contraindicated in patients with renal impairment)

Question 26

• Major risks with diarrhoea

Answer 26

dehydration and electrolyte loss

Question 27

Diarrhoea – Pathophysiology Summary

Answer 27

Treatments should address dehydration and electrolyte loss before symptomatic relief

Question 28

Cholera Toxin Mechanism of Action -

What happens when the B subunits interact with host cells via GM1 receptor

Answer 28

By interacting with GM1 they bring the a subunit into close proximity with the membrane so it can form this transmembrane relationship (expands across membrane from outside to inside)

Question 29

Cholera Toxin Mechanism of Action -

What happens when cells come into contact with cholera toxin particles

Answer 29

when cells come into contact with cholera toxin particles they recognise that and because they don’t like it they endocytose the particles by wrapping them up in membranes and moving them inside the cell

Question 30

Cholera Toxin Mechanism of Action -

What does the host cell do to the endocytosed complex

Answer 30

Proton pumps acidify the CT-containing endocytic vesicle and acidification leads to dissociation between a and b sub units. leaving alpha sub unit stuck into membrane of endosomes with A1 part sticking out

Question 31

Cholera Toxin Mechanism of Action -

G proteins are important in..

Answer 31

G proteins are important in transducing signal from cell membrane receptor to intracellular action