Mechanisms of Diarrhea
I. Introduction- Diarrhea & constipation are two of the most common complaints in medicine. Both are caused by intestinal malfunction.
A. Diarrhea is a combo of two things:
1. passage of greater than normal number of stools (>200 g/day)
2. stools of decreased form as compared with normal
B. Constipation- difficult or painful passage of hard, dry stools…unrelated to how long it has been since the last stool was passed. Spaces of up to several days are normal between stools.
C. Normal Intestinal function- 98% of water is removed from the lumen, leaving only <200 ml/day.
II. Abnormal intestinal mechanisms leading to diarrhea-
A. Abnormal electrolyte and water transport- most common mechanism of acute diarrhea (90%) is increased secretion of fluid and electrolytes out onto the mucosal surface of the gut. This is especially important with infection.
B. Presence of intraluminal osmotic factors- unabsorbed substances in the gut ( Mg antacids or laxatives like milk of magnesia, lactose in disaccharidase deficiency) pull water into the gut. Also, small bowel Dz (tropical and non-tropical sprue and bacterial overgrowth) can inhibit absorption of food and cause watery diarrhea.
C. Disorders of motility- more common in chronic diarrhea (irritable bowel syndrome, inflammatory bowel Dz, Crohn’s Dz).
III. Microbial virulence properties-
A. Adherence- to the mucosal surface
1. fimbriae or pili for Enterotoxigenic E. coli (ETEC). These structures are finger-like projections from the microbe’s surface which allow attachment to specific small bowel receptors. The fimbriae are heat labile, they are under plasmid control, and they show species specificity (humans aren’t affected by the same ones as other animals.) Purified fimbriae (a.k.a. colonization factor antigens) may be used for immunization against ETEC. ETEC is a major cause of pedi diarrhea in developing tropical and semitropical regions and can also ambush visitors to those regions (“travelers’ diarrhea”).
2. Attachment with local enterocyte damage for Enteropathogenic E. coli (EPEC). EPEC can be identified by flagellar, somatic, and capsular Ag serotypes or by DNA probes and adherence to tissue culture cells (Hep-2 or HeLa cells). They cause diarrheal outbreaks in hospital nurseries.
3. Sucking disc of Giardia lamblia allows nonspecific attachment to small bowel mucosa. Giardia commonly causes diarrhea in people who visit the mountains of N. America or Russia and in infants in daycare.
B. Cytotoxicity- is due to an exotoxin (released by normal microbe metabolism) causing necrosis of intestinal mucosa. Bugs that can do this usually cause more severe illnesses.
1. Shigella dysenteriae 1 (shigella bacillus)- is a protein synthesis inhibitor, and a major cause of fatal diarrhea in developing areas if antimicrobials aren’t given. A closely related toxin is made by E. coli (0157:H7) and causes hemorrhagic colitis. Both of these toxins are important to the production of hemolytic uremic syndrome (which causes hemolytic anemia and renal failure).
2. Clostridium difficile (toxins A & B)- is found in the colon of ~4% of adults. Overgrowth of the microbe causes necrosis of the colonic mucosa, diarrhea, and fever, a condition known as “pseudomembranous colitis.” Diarrhea caused by this bug is usually associated with the following:
a. hospitalization for >72 hours
b. antibiotic Tx within the past two months. “antibiotic associated colitis”
c. exogenously acquired inf. with cytotoxigenic C. difficile.
3. Other agents:
a. Aeromonas hydrophila- causes acute and persistent diarrhea worldwide.
b. Entamoeba histolytica- causes diarrhea (amebiasis) in areas where hygiene is low and can form liver abscess, especially in males.
C. Intestinal secretogogues-
1. Humoral agents- E series prostaglandins, vasoactive intestinal peptide (VIP- produced by villous adenoma of the colon), and calcitonin all facilitate intestinal secretion.
2. Detergents- stimulate colonic electrolyte and water secretion.
a. bile acids- in the form of bile salts.
b. Laxatives that contain phenolphthalein (Exlax)
3. Bacterial enterotoxins (exotoxins)- change intestinal transport by stimulating cyclic nucleotides, but the histology of the gut is normal.
a. ETEC-
1) heat labile enterotoxin (LT) works like this:
The binding (B) subunit attaches to GM1 ganglioside in the small bowel.
|
The active (S or A) subunit enters the cell interior to activate adenylate cyclase (cAMP).
|
Ca++ activates calmodulin and facilitates the phosphorylation of membrane proteins (protein kinase).
|
Increased secretion of Cl- and HCO3- and decreased absorption of Na+.
|
Water follows.
|
Watery diarrhea
2) Heat stable enterotoxin (ST) causes guanylate cyclase stimulation, resulting in process similar to that above.
c. V. cholerae enterotoxin- also has the B and A subunits and activates adenylate cyclase.
d. Y. enterocolitica
e. Aeromonas
f. C. difficile
g. Bacillus cereus
4. Immune and inflammatory mediators (bradykinin, histamine, cytokines, serotonin) appear to stimulate active intestinal secretion.
D. Invasiveness- different bugs cause variable degrees of invasion, inflammation and fever. In these cases, diarrhea is produced by the release of cytokines and mast cell degranulation. High motility and secretory diarrhea are induced.
1. Superficial invasion- Shigella and Campylobacter. Clinically, you see fever, abdominal cramps, dysentery (bloody, mucoid stools) without bacteremia. Both these bugs stimulate the release of chemotactic factors which attract phagocytes, leading to crypt abscesses.
2. Deep invasion- Salmonella. The host’s leukocytic response determines clinical findings.
a. non-typhoid Salmonella- polymorphonuclear leukocytic exudate is assoc. with phagocytosis, limited spread and gastroenteritis.
b. S. typhi (typhoid bacillus)- mononuclear leukocytes are produced with carriage of bacteria into portal circulation, leading to bacteremia.
3. Phagocytes, mast cells, and T lymphocyte-mediated events lead to release of inflammatory mediators such as histamine, bradykinin, cytokines, substance P and VIP. These mediators stimulate secretion and high motility in the gut , leading to diarrhea.
E. Less clear mechanisms-
1. Malabsorption- especially of disaccharides in the small bowel. May be caused by rotavirus, Norwalk, or Giardia.
2. Motility change- delayed gastric emptying may be caused by rotavirus or Norwalk.
IV. Clinical aspects of diarrhea-.
A. small bowel versus large bowel diarrhea- normal colon in the adult is a 2-6 L reservoir.
1. volume and frequency of stools- diarrhea from the small bowel will fill up the colon before emptying, so you will see only a few stools that are huge in volume. Diarrhea from the colon empties frequently before filling up, so you will see many stools of small volume.
2. upper vs. lower abdominal complaints- small bowel problems tend to cause pain higher up in the abdomen. Colon problems cause pain lower in the abdomen.
3. Other signs of colitis-
a. fecal urgency
b. tenesmus- straining on defecation from rectal sphincter spasm secondary to local inflammation.
c. dysentery
B. dehydration-
1. Secretory diarrhea-
2. Diarrhea + vomiting = rotavirus
3. Oral rehydration therapy (ORT) in diarrhea- used to Tx and prevent complications of dehydration.
a. Works like this: glucose, amino acids, and peptides couple with Na+ during absorption in the gut. Then water passively follows.
b. Problems with ORT-
- Na+ content is high. ~90 mmol/L which is necessary for active cholera, but if the pt has a milder form of diarrhea, the high Na+ load can cause hyperosmolality and hypernatremia with resultant seizures, unconsciousness &/or death. Make sure that the pt drinks equivalent volumes of free water. (In the U.S., the ORT solution usually comes with the water already added.)
- Diarrhea isn’t improved. In fact, it may get a little worse, but when you are trying to avoid death, this is okay.
- Lacks calories. A child may have a 60% reduction in caloric intake during diarrhea due to lack of appetite. If a child is already malnourished, this can be a real problem. Adding more glucose increases osmolality of the ORT, so cereal -based ORTs have been developed to provide calories through starch. The cereal-based ORTs must be used rapidly to avoid bacterial contamination.
C. Clinical features of illness-
1. Fever- inflammation, usually intestinal invasion. May be caused by invasive bacteria, C. difficile, or viruses.
2. Vomiting-
a. food poisoning from a preformed enterotoxin (Staph. aureus or Bacillus cereus) with incubation time <4 hrs.
b. if vomiting is the predominant manifestation, think virus (rotavirus in infants <3 y.o.a. or Norwalk in older kids and adults) with incubation time >8 hrs.
3. Dysentery- Most commonly Shigella or Campylobacter jejuni. Less commonly- Salmonella sp, Aeromonas sp, Vibrio parahemolyticus, Entameba histolytica, or inflammatory bowel Dz.
4. Bacteremia- Salmonella sp, Campylobacter sp, Yersinia enterocolitica.
5. Lactase deficiency- viral agents, ETEC, or Giardia.
6. Persistence of symptoms- If >14 days, think Giardia, Cryptosporidium, Cyclospora, bacterial overgrowth of the small bowel, lactase deficiency, bacterial agents or Brainerd diarrhea. Brainerd diarrhea was relatively recently described in Brainerd, MN. Agent remains unidentified, but is apparently transmitted through unpasteurized milk and untreated water. Pt will have a (-) GI work-up, lymphocytic infiltration of colonic mucosa, and diarrhea lasting for up to 3 yrs. Self-limiting.
V. Immunology of enteric infections-
A. antitoxic vs. antibacterial- immunity can be directed against toxins produced by the microbe, or against the causative microbe itself.
B. Natural immunization vs. vaccines- Vaccines may be pursued if :
1. there is an identifiable and definable population at predictable risk.
2. The condition is medically important.
3. The responsible organism has a limited number of antigenic types.
4. Immunity occurs naturally through normal exposure to the organism.
C. Organisms with great promise for immunoprophylaxis: rotavirus- (#1 cause of infant death in underdeveloped countries), ETEC, Shigella, and Vibrio cholerae.
D. Non-typhoid Salmonella (common cause of food-borne diarrhea) isn’t a candidate for vaccine since there are >2,000 antigenic types.
Tags: Abnormal electrolyte, Bacillus cereus, Bacterial enterotoxins, bile acids, constipation, Cytotoxicity, cytotoxigenic, Enteropathogenic, Giardia lamblia, intestinal function, irritable bowel syndrome, Microbial virulence, Salmonella, stools
