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Lecture 16: Diarrhea

Mucosal Resistance
Na Absorptive Mechanism
Specialized Absorption
Mucosal Resistance: Very Leak

Na Absorptive Mechanism:
-Na-H Exchange

Specialized Absorption: Ca/Fe
Mucosal Resistance
Na Absorptive Mechanism
Specialized Absorption
Mucosal Resistance: Very Leak

Na Absorptive Mechanism
-Na-H Exchange
-Electrogenic Na

Specialized Absorption
Mucosal Resistance
Na Absorptive Mechanism
Specialized Absorption
Mucosal Resistance: Moderately Leaky

Na Absorptive Mechanism:
-Na-H Exchange
-Electrogenic Na

Specialized Absorption:
Bile salts
Vitamin B12
Lactose Intolerance
Simple diagnosis established by elimination of lactose and resolution of symptoms
Lactose tolerance test:
- Load with 50gm of lactose
- Rise in blood sugar of < 20mg/dl
- Duplicate GI symptoms
Osmotic Diarrhea
Pathophysiologic cause
•Accumulation of poorly absorbed solutes in lumen - usually carb - which has osmotic activity and pulls water from GI tract into lumen
•Unabsorbed sugars that enter colon are metabolized by colonic bacteria to short chain fatty acids which have osmotic activity & lower stool pH
Osmotic Diarrhea: Causes
Disaccharidase deficiencies - Lactose intolerance
➢Lack enzyme lactase to eliminate lactose and thus enters colon, fermented by bacteria and leads to diarrhea

Intake of poorly absorbed or nonabsorbable sugars - artificial sweeteners

Intake of antacids & cathartics

Some laxatives
Lactose Tolerance Breath Hydrogen Test
Ingest lactose
Measure breath hydrogen over several hours
Spike in Hydrogen release suggests lactose intolerance
Why is the pH of stool low?
When CHO reaches the bacteria of the colon it is fermented
Short chain fatty acids are produced
Most of the fatty acids are absorbed
From the fermentation, the stool pH drops to <6
Acid stools suggest CHO fermentation in the colon
C. difficile
Anaerobic, Gram-positive, Spore-forming bacillus

Normal intestinal flora in 5% of adults
Found in 20% of hospitalized patients
Usually (but not always) associated with antibiotics
Sometimes associated with cancer chemotherapy

Spectrum of mild disease to fulminant colitis
Caused by toxin elaborated by C. difficile
C. difficile: Pathogenesis
Disruption of normal flora
Colonization with C.difficile
Release of toxin
Damage to mucosa
Inflammatory response

Toxin A
Causes fluid secretion
Mucosal damage
Intestinal inflammation
Toxin B
Not toxic in animals but may be toxic in humans
1000 times more cytotoxic than toxin A

Can see thumbprinting
Clinical Clues foe Osmotic Diarrhea
Symptoms stop when patients fasts or discontinues ingestion of product

Stool osmolarity gap is elevated
➢Ions account for only a fraction of osmoles in stool water
➢Increased gap associated w/ ingestion of poorly absorbed substances

Stool pH is low - b/c short chain fatty acids produced from bacterial metabolism of carbs entering colon
Secretory Diarrhea: Pathophysiologic cause
Passage of voluminous stools b/c of active small bowel secretion of isotonic fluid far in excess of colonic absorptive capacity

Colon can also be induced to secrete fluid & electrolytes

Ions account for most of osmoles in diarrhea - small osmotic gap
Secretory Diarrhea: Clinical Signs
Voluminour diarrhea
Osmotic gap small < 50
Persists even when fasting
Absence of mucus, pus or blood in stool
Bile acid induced usually responds to treatment w/ cholestyramine
Hospital Acquired Diarrhea
Primary cause of nosocomial infectious diarrhea in developed countries

Salmonella, shigella, campylobacter and protozoa are almost never positive in stool assays for enteric pathogens in hospital-acquired diarrhea
Secretory Diarrhea: Causes
Non-invasive diarrhea
- Viruses (Norwalk)
- Giardia
- Cryptosporidia
- Cholera, E.coli - most common form of traveler's
Invasive diarrhea:
- Salmonella
- Shigella
- Invasive E. coli
- C. diff

Reduction of mucosal surface area: Celiac disease flattens brush border

Inflammation - overlap with exudative

Dysregulation - tumors, ZE, VIP secreting tumor, Diabetes mellitus

Circulating secretagogues - inhibit absorp or produce secretion (rare)

Luminal Stimuli (bile acids, fatty acids, enterotoxins)
Vibrio Cholera
Active secretion of Cl and Na & inhibition of NaCl absorption:
- In villous enterocytes, cyclic adenosine monophosphate (AMP) inhibits the neutral coupled absorption of sodium and chloride. The glucose or substrate-stimulated sodium transport mechanism is unaffected.
- In crypt enterocytes, however, cyclic AMP activates protein kinase A to open chloride channels, resulting in chloride and water secretion.
- The chloride channel has been demonstrated to be the cystic fibrosis transmembrane regulator (CFTR), which is phosphorylated and activated by protein kinase A.
- Cholera toxin may also influence mucosal transport by effects on enteric nerves and paracrine cells.
Water follows

Pathogens don't cause morphological damage, invade or impair Na dependent solute absorption
Oral rehydration therapy
Oral Rehydration Therapy
The basic principle is that glucose (and other substrates, such as amino acids) are cotransported with sodium into enterocytes in the small intestine.

Unlike other mechanisms of sodium absorption, cotransport is intact in many forms of secretory diarrhea; thus, stimulation of sodium absorption by cotransport can be used to enhance sodium absorption, even in the presence of bacterial toxins.

The glucose-sodium cotransport leads to deposition of sodium in the basolateral space as a result of glucose absorption.
- Chloride must enter across the tight junction for sodium to remain on the basolateral side of the enterocyte.
- Otherwise, sodium diffuses back to the lumen through the tight junction in response to the electrical potential generated by cotransport, and no net sodium absorption would occur.

The duodenum and jejunum are the only areas of the gut in which sufficient chloride can permeate across tight junctions to allow cotransport to result in net sodium chloride (and water) absorption.

An alternative mechanism for glucose-stimulated sodium absorption is solvent drag.
- Removal of glucose from the luminal fluid by cotransport results in generation of an osmotic gradient between the lumen and the basolateral space.
- This generates a flux of water across the tight junctions, which entrains sodium and chloride ions by solvent drag.
- This mechanism also can only occur in the proximal small intestine because paracellular permeability is restricted in the ileum and glucose is not absorbed in the colon.
- In healthy humans, this alternative mechanism accounts for roughly two thirds of the total amount of glucose-stimulated sodium absorption. The situation may be different if paracellular permeability for water or electrolytes is altered by disease
E.coli 0157:H7 (EHEC)
30-95% have bloody diarrhea (segmental colitis)
2-7% develop the hemolytic-uremic syndrome (mostly children)
Overall mortality rates 1-35%
Epidemic and sporadic cases
Food: hamburger and meat; requires very low inoculum
Person to person transmission
Daycare centers and nursing homes
Exudative Diarrhea/Inflammation
Overlaps w/ secretory

Pathophysiologic cause
•Mucosa cannot function properly since inflamed or ulcerated
•Less surface area to absorb fluid, electrolytes & nutrients
•Inflammation & ulceration causes passage of mucus, blood, & protein into gut/lumen

•IBD - Crohn's, UC
•Infectious: salmonella, shigella, CMV, amebiasis
•Radiation colitis, ischemic colitis

Clincial Clues/ Tests Diagnosis
•Passage of blood & mucus
•Abrupt onset suggests infectious etiology
•RBCs or WBCs in stool
•Stool culture for bacteria & O & P
•Stool for C.Diff
Steatorrhea/Fatty Diarrhea: Symptoms and Diagnosis
Pathophysiologic cause: Presence of fatty acids in colon causing secretion of fluid & electrolytes

•Foul smelling, frothy stool
•Difficult to completely flush
•Oil droplets in stool

Clinical clues/Test
•72 hr stool collection for fecal fat
•Stool sudan stain for fat droplets
•Stool volume decreases when patient is fasting

Some imaging:
•Abdominal CT - rule out pancreatic disease
•Small bowel X-ray - rule out structural/mucosal disease
•Small bowel aspirate - rule out bacterial overgrowth
•Serological studies - rule out celiac disease
Ulcerative Collitis vs Crohn's Disease
- DIFFUSE mucosal inflammation limited to the colon
- almost always affects rectum
- may involve all of part of the colon

- PATCHY transmural inflammation
-may affect any part of the GI tract
- metastatic cutaneous crohns disease - noncaseating granulomatous infiltration of the skin occurs at sites unconnected to the GI tract
- fistulas
Acute Infectious Colitis vs IBD:
Duration of symptoms
Onset of symptoms
Acute Infectiopus:
Duration of symptoms: <2 weeks
Onset of symptoms: abrupt
Platelets: normal
Hct: normal
Biospy: neutrophils predominate

Duration of symptoms: >4 weeks
Onset of symptoms: insidious
Platelets: >450,000
Hct: low
Biospy: mixed infiltrate, abnormal crypt achitecture, increased lymphoid aggregates, basal plasmacytosis
If a patient with diabetes mellitus comes in complaining of fecal incontinence it is important to do what?
Distinguish whether it is actually incontinence or diarrhea.

If it is diarrhea you must distinguish between steatorrhea and chronic watery diarrhea.
- Steatorrhea may be caused by coexisting small-bowel bacterial overgrowth, celiac disease, or pancreatic exocrine insufficiency.
- Watery diarrhea has been attributed to dysregulation by the enteric nervous system as a manifestation of diabetic autonomic neuropathy.
Verner-Morrison syndrome
Vasoactive intestinal polypeptide (VIP)-secreting tumors produce the Verner-Morrison syndrome, also known as pancreatic cholera syndrome, or watery diarrhea, hypokalemia, and achlorhydria syndrome.

VIP produces a secretory state in the intestine by raising enterocyte cyclic AMP levels, causing chloride secretion and inhibiting sodium absorption.

Treatment with resection is ideal, but injection of octreotide, the somatostatin analogue, has allowed good control of symptoms in many patients
Carcinoid Syndrome
Rare syndrome in which a carcinoid tumor must secrete mediators capable of producing symptoms and must be either metastatic to the liver or lung or primary at a site where direct access to the systemic venous circulation (bronchus, ovary) exists.

The liver is capable of inactivating many of the mediators that may be produced by tumors in the intestine.

After access to the systemic circulation has been achieved, the intensity of symptoms tends to be related to the tumor burden and the circulating levels of mediators.

Progression of tumor is slower than that of carcinomas arising in the intestine; a course of up to 10 years from the onset of symptoms until death is not unusual.

Diarrhea may be caused largely by hurried intestinal transit rather than by development of a secretory state, and usually is of only moderate volume.
Medullary carcinoma of the thyroid
Productes calcitonin (CT), prostaglandins (PG), and other secretagogues. It often presents as part of multiple endocrine neoplasia type 2 (2a) or 3 (2b).

Calcitonin can produce a secretory state; prostaglandins and other mediators can be associated with rapid transit, giving the diarrhea a multifactorial etiology.

Treatment with nonsteroidal anti-inflammatory drugs or opiates can control such diarrhea, but the prognosis for survival is poor when medullary thyroid carcinoma presents with diarrhea.
Migratory necrotizing erythema usually arise from what?
Drugs that can induce diarrhea
Antineoplastic agents
Anti-inflammatory agents(NSAIDs)
Acid-reducing agents(H2recept,PPIs)