12. Diarrhea

• Diarrhea pathophysiology relates to hypovolemia and mechanisms of diarrhea.

Hypovolemia: Causes & Consequences

• Hypovolemia is a state of low ECF volume.
• Causes of hypovolemia:
  • Diarrhea and luminal fluid sequestration
  • Hemorrhage
  • Vomiting
  • Excessive sweating
  • Salt and water deprivation
  • Renal disease
• Consequences of hypovolemia:
  • Reduced blood perfusion
  • Tissue Ischemia leading to lactic acid production
  • Metabolic acidosis
  • Circulatory collapse
  • Hypotension
  • Peripheral vasoconstriction
  • Loss of consciousness.

Mechanisms of Diarrhea

• Five main mechanisms of diarrhea exist.
• These include; filtration secretion, osmotic diarrhea, secretory diarrhea, inflammatory diarrhea and abnormal motility

Filtration Secretion

• Involves abnormal Starling forces at submucosal capillaries.
• Normal Starling forces maintain equilibrium in the submucosa
• At the arterial end of the capillary, hydrostatic pressure (HP) exceeds colloid osmotic pressure (COP), resulting in net fluid movement out of the capillary.
• At the venous end, COP exceeds HP, leading to net fluid movement into the capillary.
• Pathology occurs when net interstitial Starling forces at the submucosa exceed +15 mm Hg
• Disrupts epithelial tight junctions, especially at villus tips
• Increases submucosal fluid pressure which dissects between epithelial cells.
• Occlusion of venous return from the intestine increases hydrostatic pressure, potentially due to volvulus or torsion.
• Portal hypertension, resulting from heart failure, reduces venous flow from the liver, increasing back pressure.
• Excessive volume expansion with IV fluids elevates capillary hydrostatic pressure.
• Lymphatic obstruction, caused by lymphatic disease, inflammation, or cancer, increases hydrostatic pressure due to blocked lymphatic drainage.
• Interstitial fluid dissects between epithelial cells, PLE (protein-losing enteropathy) occurs.

Osmotic Diarrhea

• Occurs due to osmotically active molecules, such as sugars, VFAs, and certain ions, drawing extracellular fluid into the intestine
• Extracellular fluid moves passively into the intestine in response to an intraluminal load of osmotically active molecules (e.g., sugars, amino acids).
• Carbohydrate overload: Increased CHO to large intestine, leading to increased VFA production
• Grain overload and lactose intolerance are common causes.
• Villous atrophy: Many infectious agents cause osmotic diarrhea by destroying the villous epithelium, decreasing brush border enzymes and surface area, leading to maldigestion and malabsorption.
• Diarrhea results from nutrients and water bypassing the small intestine and exceeding the absorptive capacity of the large intestine, accompanied by excessive fermentation.

Secretory Diarrhea

• Bacterial enterotoxins activate intracellular cyclic nucleotides (cAMP, cGMP) in the epithelium.
• Inhibition of electroneutral NaCl absorption at the villi occurs,
• Add glucose to oral rehydration solutions to enhance NaCl and H2O absorption.
• Na+-coupled substrate absorption remains unimpaired, and the brush border enzyme remains intact.
• Stimulation of electrogenic Cl- and HCO3- secretion at the crypts also occurs.

Inflammatory Diarrhea

• Caused by inflammation due to the immune response to attaching/invasive infectious agents or allergenic/autoimmune diseases.
• Osmotic diarrhea results from villous atrophy.
• Filtration secretion results from obstructed flow due to edema, vasoactive cytokines, and inflammatory infiltrate, altering Starling forces.
• Secretory diarrhea results from enterotoxins and inflammatory mediators stimulating intracellular second messengers.

Abnormal Motility

• Hypermotility increases digesta transit
• Flaccid, hypomotile intestine is typical of most common diarrheas.
• Caused by drugs (laxatives, parasympathomimetics) and irritable bowel syndrome.
• Infection and/or inflammation in the gut can cause muscle spasms, cramping, pain, and increased borborygmi

Diarrhea Caused by Enteric Pathogens

• Certain pathogens have well-defined diarrheogenic mechanisms.
  • Enterotoxigenic E. coli (ETEC) causes secretory diarrhea.
  • Rotavirus and coronavirus cause osmotic diarrhea.
• Agents that produce significant inflammation cause diarrhea in several ways.
  • Salmonella causes enterotoxigenic, inflammatory (invasive infection).
  • Cryptosporidia causes villous atrophy and inflammation.

Fluid Retrieval During Hypovolemia & Colonic Salvage

• The sympathetic nervous system inhibits enteric effector neurons and preganglionic PS neurons, increasing NaCl absorption and decreasing Cl- and H2O secretion.
• Enkephalinergic interneurons increase NaCl absorption and decrease Cl- and H2O secretion, which slows segmentation passage.
• The renin-angiotensin-aldosterone system is activated.
• Angiotensin II promotes sympathetic transmission to the intestine.
• Aldosterone increases electrogenic Na+ absorption at the large intestine.

Colonic Salvage

• Colonic salvage is the reserve capacity of the large intestine for fluid absorption.
• Colonic disease typically results in diarrhea, but small intestinal disease may not necessarily produce diarrhea because of colonic salvage.
• The colon has a large reserve capacity for electrolyte and fluid absorption
• One component of reserve capacity is the microbial digestion of nutrients that bypass the small intestine, increasing NaVFA and water absorption (requires colonic flora to generate VFA).
• This process is not available to neonates who lack gut microbes, and is lacking robust gut flora suitable for diarrhea.