Diarrhoea

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:
  • Chronic inflammation (e.g. Johnes disease).
  • Immunologically mediated reactions (e.g. eosinophilic enteropathy).
  • Neoplasia (e.g. intestinal lymphoma).
• 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.
  • For more information on the pig, see transmissable gastro-enteritis in the pig.
• 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.
  • The colon is able to resorb up to 3-4 times the volume normally presented from the small intestine.
• 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.