Diarrhoea

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Introduction

  • Defined as "an increase in volume and fluidity of faeces, and increased frequency of defaecation".
    • Associated with malabsorption of fluid and electroyles in the intestines.
  • The precise pathogenesis of diarrhoea in many individual diseases is not well defined.
    • Four major mechanisms are known to exist.
      • One or more of these may operate in many diseases.

Interference with normal mucosal cell transport processes

Normal intestinal absorption and secretion

  • Normal intestinal water absorption and secretion is mainly due to passive osmotic forces created by active solute transport.
    • The sodium ion (Na+) is the most important solute.
      • Is actively absorbed from the intestine.
      • Is largely responsible for the passive absorption of water.
  • Active Na+ absorption from the intestine results from a combination of processes.
    1. Na+ is secreted from intestinal epithelial cells into the underlying interstitium
      • This is ATPase dependent
      • Creates a gradient for uptake of Na+ from the intestinal lumen.
    2. There is coupled Na+ and Cl- absorption.
      • Na+ and Cl- are activily absorbed at the luminal surface of the cell.
        • The mechanism for this is dependent on adenyl cyclase activity.
    3. Na+ is also absorbed in association with glucose and some amino acids (i.e. coupled).
      • This is also energy dependent.
  • Once absorbed into the intestinal epithelial cells by these coupled mechanisms, Na+ is pumped out by the basal and lateral primary pumps.
    • This increases the gradient for water absorption.
  • These overall absorption mechanisms operate primarily on mature villus absorptive cells and colonic surface cells.
    • The small intestinal crypts are lined by rapidly dividing and relatively immature cells.
      • Although there is primary active Na+ absorption there is also active secretion of Na+, Cl-, HCO3-, and therefore H2O.
        • Consequently there is an overall balance of secretion into the crypt - normal intestinal secretions.
      • The same potential secretory mechanisms probably exist in the villus cells.
        • These are grossly outweighed by absorptive mechanisms.
      • Considering both villus and crypt mechanisms, there is net absorption of Na+ and H2O.

Secretory Diarrhoeas

  • The overall balance of the absorptive and secretory mechanisms above is shifted in a number of diseases.
    • There is net secretion of Na+ and H2O into the lumen of the intestine.
      • “Secretory” diarrhoeas.
  • The best known secretory diarrhoeas are those caused by the enterotoxin producing strains of bacteria.

Enterotoxin Producing Strains of Bacteria

  • E.g. Vibrio cholerae, E. coli.
  • Organisms adhere to the surface of intestinal epithelial cells and secrete their enterotoxins.
    • Enterotoxins are absorbed into cells and interfere with intracellular enzymes and metabolism.
  • The heat labile enterotoxin of E. coli and cholera toxin interfere with adenyl cyclase activity.
    • Result in increased intracellular levels of cAMP.
    • Increased cAMP interferes with chloride coupled sodium transport
      • Promotes Na+, Cl- and hence H2O secretion from the epithelial cells.
      • The overall balance is shifted and the intestine becomes a net secretor of fluid.
    • The increased cAMP levels probably act via a number of other intracellular processes including:
      • Activation of protein kinases.
      • Increased intracellular Ca++ levels.
      • Calmodulin stimulation.
  • Other enterotoxins may act by other mechanisms.
    • E.g. the heat stable toxin of E. coli acts by guanyl cyclase and increased cGMP.

Other types of disease processes

  • Other types of disease processes may also interfere with mucosal transport.
  • Prostaglandins, released during inflammation, and intestinal polypeptides (e.g. VIP) act via adenyl cyclase and increased cAMP.
  • Acetylcholine stimulation from the parasympathetic nervous system promotes secretion via increased intracellular Ca++ levels.

Treatment

  • Chloride coupled mechanisms of Na<sup+ (and H2 are affected as described above.
    • However, other mechanisms remain intact provided the epithelial cells are not destroyed.
      • E.g. glucose and primary active transport.
  • It is therefore possible to “drive” the surviving absorptive processes.
    • Forms the basis for oral fluid and electrolyte replacement therapy.
      • A mixture of salt, sugar and water is used to treat diarrhoea.

Alterations in structure/permeability

Inflammation/ Infiltration

  • The absorptive capacity of the intestine is dependent on intestinal surface area.
  • Many diseases cause massive cellular infiltration into the small intestinal lamina propria, resulting in:
    • Stunting and fusion of villi.
    • Loss of surface area.
    • Overall decreased absorptive capacity.
  • The cellular infiltrate may result from:
  • Inflammatory or reactive processes immediately below the epithelium may provoke interference with epithelial transport processes and increase the tendency to diarrhoea.

Acute Destructive Enteropathies

  • Invasive bacterial infections such as Salmonellosis result in epithelial destruction and loss of surface area.
  • There is also active exudation of extracellular fluids from the eroded/ ulcerated mucosal surface.
    • Exacerbated by the increased vascular permeability associated with inflammation.
    • Prostaglandin release associated with inflammation may also provoke secretion from surviving epithelial cells.
  • The presence of blood and mucosal shreds in watery faeces is known as dysentery rather than diarrhoea.

Osmotic diarrhoea

  • If non-absorbable solutes accumulate in the gut lumen, there will be retardation of water and electrolyte absorption and diarrhoea will occur.
    • Large amounts of osmotically active solutes will cause net movement of water from the plasma into the lumen.
  • Seen in animals deficient in specific brush border enzymes.
    • E.g. lactase deficiency.
      • Feeding lactase deficient animals on milk means that lactose will remain in the lumen as an osmotically active solute rather than being broken down to glucose and galactose.
        • Provokes diarrhoea.
    • The presence of immature epithelial cells on villi will also cause an osmotic type of diarrhoea.
      • Lack their normal brush border enzymes.
  • Many laxatives act in this way.
    • E.g. those containing magnesium.

Derangement of intestinal mobility

  • In some cases diarrhoea is related to intestinal mobility.
  • Some pharmacologically active substances stimulate intestinal motility.
    • E.g prostaglandins.
    • Decreases the transit time for intestinal contents.
      • Less absorption occurs.
    • May cause diarrhoea.
  • Intestinal stasis may also stimulate diarrhoea.
    • Appears to be due to excessive bacterial multiplication in the intestinal contents.
      • "Small intestinal bacterial overgrowth" (S.I.B.O.) .
      • Results in the production of large amounts of osmotically active substances in the intestinal lumen.

An Example of the Mechanisms of Diarrhoea

  • In any individual disease associated with diarrhoea, a combination of two or more of the mechanisms above may be involved in the disease pathogenesis.
  • For example, transmissible gastroenteritis (TGE).

Transmissable Gastro-Enteritis (TGE)

  • Affects pigs, cattle and dogs.
  • Caused by a coronavirus, which attacks mature absorptive cells of the intestinal villi.
  • Gives excessive loss of surface epithelial cells.
    • Results in villus stunting and fusion in an attempt to maintain epithelial continuity.
      • Surface area is decreased.
        • Loss of absorptive capacity.
  • The intestinal crypts become hyperplastic to increase the replacement of lost epithelial cells.
    • Crypt cells are normally net secretors- there is therefore increased secretion from this source.
  • New cells move up from the crypts onto the villus more rapidly than usual.
    • Cells are immature and lack their normal brush border enzymes.
      • There is therefore an osmotic component to the diarrhoea.
  • There may be inflammation in the underlying lamina propria.
    • Prostaglandin is released, and
      • Increases intestinal motility.
      • Provokes increased secretory activity from remaining epithelial cells.


Diarrhoea in Small Intestinal Disease Only

  • When disease is present only in the small intestine, diarrhoea occurs only when the reserve capacity of the colon to resorb water is exceeded.
  • Therefore, for diarrhoea to occur, small intestinal disease must either:
    • Be severe, or
    • Occur in conjunction with large intestinal problems.
  • Some small intestinal diseases cause only weight loss.
    • May see hypoalbuminaemia and oedema in very severe cases.
    • Weight loss is due to:
      • Maldigestion.
      • Malabsorption of nutrients
        • Cannot be retrieved by colonic resorption (except in horses).

Diarrhoea in the Large Intestine

  • Diarrhoea may occur because of failure of large intestine function, e.g.
    • Colitis due to Treponema hyodysenteriae in pigs.
    • Large intestinal parasitism in the horse.
  • Mechanisms are similar to those described above.
    • Interference with mucosal transport processes.
    • Destruction or loss of surface area.


Diarrhoea Learning Resources
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