Diarrhoea 1 - Anatomy and Pathophysiology Flashcards Preview

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1
Q

Gastrointestinal Motility

A

• 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

2
Q

GI tracts own nervous system =

A

ENS (enteric nerve system)

3
Q

GI Motility

A

• increased transit time
- Increased water
absorption -> constipation

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

4
Q

Diarrhoea:

A Failure of Fluid-Handling

A

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.

5
Q

A major function of the colon is to

A

reabsorb fluid

6
Q

Two Major forms of Diarrhoea

A
  • Osmotic diarrhoea

- Secretory Diarrhoea

7
Q

-Osmotic diarrhoea

A

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)

8
Q

-Secretory Diarrhoea

A

-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

9
Q

Osmotic Diarrhoea

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

A

• 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.

10
Q

how to diagnose osmotic diarrhoea

A

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

11
Q

Secretory Diarrhoea

-Increased fluid secretion normally due to:

A

• 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

12
Q

diarrhoea can be associated with

A

• 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

13
Q

Prevalence of diarhoae

A

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

14
Q

important agent in diarrhoea

A

infection

15
Q

(Some) Infective Agents Causing Diarrhoea

A

Viruses
Bacteria
Parasites

16
Q

(Some) Infective Agents Causing Diarrhoea - Viruses

A
  • Rotavirus
  • Norwalk virus
  • Norovirus - winter sickness
  • Calicivirus
17
Q

(Some) Infective Agents Causing Diarrhoea - bacteria

A
  • Campylobacter jejuni
  • Salmonella
  • Escherichia coli
  • Shigella
  • Yersinia entercolitica
  • Clostridium difficile
18
Q

(Some) Infective Agents Causing Diarrhoea - Parasites

A
  • Cryptosporidium

- Giardia lamblia

19
Q

Cholera Toxin Mechanism of Action steps

A

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

20
Q

cholera toxin is made up of

A

6 B subunits surrounding 1 A subunit

21
Q

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

A

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

22
Q

(By way of a detour… The CFTR)

A

• 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

23
Q

Clostridium Difficile

A

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

24
Q

Clostridium Difficile -

steps to infection

A

•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

25
Q

Clostridium Difficile

• Pharmacological Treatment

A
  • Discontinue offending antibiotic
  • Metronidazole (contraindicated in patients with liver or renal impairment)
  • Vancomycin (contraindicated in patients with renal impairment)
26
Q

• Major risks with diarrhoea

A

dehydration and electrolyte loss

27
Q

Diarrhoea – Pathophysiology Summary

A

Treatments should address dehydration and electrolyte loss before symptomatic relief

28
Q

Cholera Toxin Mechanism of Action -

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

A

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)

29
Q

Cholera Toxin Mechanism of Action -

What happens when cells come into contact with cholera toxin particles

A

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

30
Q

Cholera Toxin Mechanism of Action -

What does the host cell do to the endocytosed complex

A

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

31
Q

Cholera Toxin Mechanism of Action -

G proteins are important in..

A

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