Gi Pathophysiology Lecture 4: Diarrhea

Front 1

Diarrhea is both a sign and symptom
A. As a symptom:

Back 1

1. Increased Frequency
2. Increased Volume
3. Decreased Consistency

Front 2

Diarrhea is both a sign and symptom
B. As a sign:

Back 2

Stool weight > 150 to 200 g per 24 hr
(stool water > 150 to 200 ml per 24 hr)

Front 3

Primary ions, fluid follows.

Back 3

Na+, K+, Cl- and HCO3-

Front 4

SGLT1

Back 4

Sodium/Glucose Co Transporter in the small intestine

Diarrheal illness caused by Cholera Toxin does NOT affect this transporter

Front 5

Electrolyte Handling by the Intestine

1. General concepts in transport.

Back 5

a. The intestinal epithelium is a polarized epithelium with tight junctions. Apical surface contains different elements from the basolateral surface.

b. There are active and passive transport mechanisms.

c. There are specialized membrane proteins (channels, carriers, and pumps) that serve to transport electrolytes.

d. In the intestine, Na+, K+, HCO3-, and Cl- are the primary ions whose active transport is involved in controlling fluid movement. Fluid follows the direction of electrolyte movement to maintain isotonicity between the intestinal lumen and tissue compartments.

Front 6

Electrolyte Handling by the Intestine
2. Mechanisms of Na+ absorption.

Back 6

- solute-coupled Na+ transport (permitting the absorption of nutrients such as glucose)
- electroneutral NaCl transport
- electrogenic Na+ transport+

Front 7

Electrolyte Handling by the Intestine
2. Mechanisms of Na+ absorption.

Coupled transport of Na+ and intraluminal nutrient (glucose and amino acids)

Back 7

a major mechanism for Na+ absorption in the jejunum following a meal, in addition to the bulk flow mechanism described above.

This phenomenon is the basis for treating diarrhea with sweetened saline as an effective and cheap oral replacement therapy for secretory diarrhea. In the colon Na+ is coupled with the absorption of short-chain fatty acids.

Front 8

Electrolyte Handling by the Intestine
2. Mechanisms of Na+ absorption.

Electroneutral sodium-chloride absorption

Back 8

absorption that is relatively more important in the ileum and the proximal colon and results from parallel ion exchanges (luminal Na+ for intracellular H+ and luminal Cl- for intracellular HCO3). The H+ and HCO3 form carbon dioxide and water in the lumen.

Loss of HCO3, resulting in a metabolic acidosis, is often seen in patients with diarrhea. Absence of the Cl-HCO3 exchanger is the mechanism of a rare congenital diarrhea.

Postprandially, after absorption of nutrients is complete or in the fasting state, __________ absorption is the major route for Na+ absorption in the small bowel.

Front 9

Electrolyte Handling by the Intestine
2. Mechanisms of Na+ absorption.

Electrogenic Na+ transport

Back 9

is found all along the intestinal tract, but plays a relatively more important role in the distal colon. The Na+-K+-ATPase at the basolateral membranes of the absorptive cells pumps three Na+ ions out in return for every two K+ ions into the enterocyte resulting in the enterocyte being electrically negative compared to the intestinal lumen. Na+ moves down the electrical and chemical gradient from the intestinal lumen into the cell interior and is pumped out into the intracellular space. The intraluminal Na+ concentration decreases along the proximal to distal axis from 140 mM in the jejunum to 50 mM in the colon.

Front 10

Electrolyte Handling by the Intestine
3. Mechanisms of Potassium Transport.

85% of ingested K+ is absorbed in the small intestine via diffusion through

Back 10

the gap junctions

Front 11

Electrolyte Handling by the Intestine
3. Mechanisms of Potassium Transport.

Active electroneutral K+ absorption occurs in the

Back 11

distal colon, mediating 5-7% of ingested K+.

Front 12

Electrolyte Handling by the Intestine
3. Mechanisms of Potassium Transport.

Potassium secretion is a function of the....

Back 12

...colon and not the small intestine

The colon, but not the small intestine, is an aldosterone sensitive epithelium. Aldosterone increases Na+ absorption and K+ secretion in the colon and is an important compensatory mechanism for dehydration.

Front 13

Electrolyte Handling by the Intestine
4. Mechanisms of Chloride Secretion.

Electrogenic chloride secretion is found in

Back 13

all segments of the GI tract from the duodenum to the distal colon, reflecting the common need to maintain hydration of lumenal contents.

Chloride secretion also involves the Na-K-ATPase. As a result of the electrochemical gradient, this cell accumulates Cl- in large concentrations via the Na-K-2Cl transporter (basolateral membrane).

Chloride secretion is effected when channels are opened by regulatory agonists. One such chloride channel in the apical membrane is the cystic fibrosis gene product, CFTR

Front 14

Electrolyte Handling by the Intestine
5. Mechanisms of Bicarbonate Secretion.

HCO3 secretion is coupled with ____ recycling at the apical membrane

Back 14

Cl- recycling at the apical membrane (via Cl transport through CFTR), or may occur independent of Cl- recycling (via HCO3 trasnport through CFTR)

Front 15

Electrolyte Handling by the Intestine
6. Other Factors that Regulate Fluid Handling.

Absorption of fluids and electrolytes is dependent upon

Back 15

the duration of contact of the luminal contents with the mucosa, which is in turn dependent on intestinal motility.

Increases in intestinal motility (e.g., secondary to hyperthyroidism) may result in diarrhea.

Opiates appear to increase water and electrolyte absorption by decreasing segmental muscular contractions, which retard transit of colonic contents and increase the duration of contact of the luminal contents with the mucosa.

Front 16

Overproduction of hormones and neurotransmitters that stimulate secretion, observed in a number of tumors (carcinoid tumors secrete serotonin and VIPomas secrete Vasoactive Intestinal Peptide) will result in

Back 16

diarrhea.

Front 17

Analogues of hormones that stimulate net absorption (e.g., octreotide a somatostatin analogue), on the other hand, have proved to be a potent _________

Back 17

antidiarrheal agent in some secretory diarrheal illnesses

Front 18

Electrolyte Handling by the Intestine
7. Intracellular signaling mechanisms.

In general, increases in cAMP levels ________ Na absorption by ______ neutral brush border uptake and ________ Cl-secretion.

Back 18

In general, increases in cAMP levels INHIBIT Na absorption by INHIBITING neutral brush border uptake and STIMULATING Cl-secretion.

The classic illness involving this signal transduction pathway is cholera and is mediated by cholera toxin

Front 19

Mechanisms of Diarrhea

The simple approach.

Back 19

Enhanced Secretion.

Impaired Absorption.

Front 20

Mechanisms of Diarrhea

A more detailed approach.

Back 20

A. Excess ileal water resulting from the presence of nonabsorbable solutes in the lumen, producing an osmotic or malabsorptive diarrhea.

B. Enhanced proximal gastrointestinal tract secretion of solute and water.

C. Impaired colonic absorption due to secretion by colonocytes or damage to the colonic mucosa by inflammation.

D. Motility disorders.

Front 21

1. Osmotic Diarrhea

The osmotic diarrheas are caused by the ingestion of ___________

Back 21

poorly absorbed solutes that drag water with them through the small intestine and into the colon.

In the proximal small bowel, poorly absorbed solutes drag water and salt into the lumen.

The severity of the resulting diarrhea is reduced by the efficient active ion transport mechanisms of the ileum and colon.

Front 22

Clinical Definition of Osmotic Diarrhea.

Back 22

1. Diarrhea stops when the patient fasts.

2. "Osmotic Gap" on stool analysis. (>100 = osmotic gap)

Osmotic gap = 290 - 2(Na+stool + K+stool)

Front 23

Causes of Osmotic Diarrhea

Name a few to illustrate general concept

Back 23

1. Disaccharidase deficiencies.

2. Glucose-galactose malabsorption. Fructose malabsorption.

3. Mannitol, sorbitol ingestion ("chewing gum diarrhea").

4. Lactulose therapy.

5. Magnesium sulfate (Epsom salt), sodium sulfate (Glauber's salt, Carlsbad salt), sodium phosphate, sodium citrate, some antacids (MgO, Mg[OH]).

6. Generalized malabsorption.

Front 24

Mechanisms of Diarrhea
2. Secretory Diarrhea

A clinical point of importance is that unless the substance causing secretion is ingested, diarrhea should continue or be only mildly reduced when the patient fasts so that stool weight is still about 200 ml/24 hours. Other clinical points are:

Back 24

(1) The stools are often very watery in consistency.

(2) The volume of diarrhea is great (greater than 2 liters per 24 hours).

(3) Stool osmolality is approximately equal to plasma osmolality.

(4) Patients with pure __________ do not usually have pus or blood in the stool or significant steatorrhea.

Front 25

Mechanisms of Diarrhea
2. Secretory Diarrhea

2 Types:

Back 25

Acute:
Infectious

Chronic:
Tumorous (secretagogue)
Infiltrating tumor (lymphoma)
Coeliac sprue
Idiopathic
Others

Front 26

Secretory diarrheas are usually due to

Back 26

stimulation of intestinal CL- and HCO3- secretion and inhibition of Na/Cl absorption by agents that increase intracellular messengers responsible for these events.

Front 27

Secretory Diarrhea.
The basic mechanism of small bowel secretion is via

Back 27

increased cyclic AMP production.

Front 28

Secretory Diarrhea.
Features (Lecture)

Back 28

- Stimulation of Net Intestinal Secretion

- No Morphological Damage

- No Impairment of Na-Dependent solute absorption

Front 29

Chronic Proximal GI Tract Secretory Disease.

Name 4 and their Mechanism

Back 29

1. Tumor producing: VIP, prostaglandin, serotonin
- Small bowel secretagogue

2. Celiac sprue
- Locally enhanced small bowel secretion

3. Zollinger-Ellison Syndrome
- Gastrin hypersecretion and diarrhea due to massive fluid generation (via gastrin secreting tumor)

4. Portal hypertension
- Increased hydrostatic and tissue pressure

Front 30

Cholera toxin binds to a specific membrane receptor, enters the cell, and activates adenylate cyclase

Consequences:

Back 30

Inc cAMP --> Inc. Anion Secretion into lumen

Inc cAMP --> Inhibits neutral NaCl absorption (coupled transport intact)

Thus, oral rehydration therapy is still very effective for treatment

Front 31

Enteric pathogens cause diarrhea by several different mechanisms

Back 31

1. Stimulation of net fluid secretion
2. Increasing propulsive muscle contractions. (less contact time)
3. Mucosal Destruction and Increased Permeability
4. Nutrient malabsorption

Front 32

Impaired Net Colonic Absorption as a Cause of Diarrhea

A. Actual Secretion
(give 3 examples)

Back 32

1. Fatty acid diarrhea.

2. Bile salt diarrhea.

3. Villous adenoma.

Both fatty acids and bile salts can be shown in in vitro perfusion preparations to turn the colonic mucosa into a secreting mucosa.

Front 33

Impaired Net Colonic Absorption as a Cause of Diarrhea

B. Decreased Absorptive Surface.
(give 2 examples)

Back 33

1. Diffuse colitis.

2. Post-resection.

Front 34

The colon is largely an absorptive organ, and the absorption of salt and subsequently water can be enhanced by circulating

Back 34

aldosterone

The colon, however, can be turned into a secreting organ under certain pathologic situations

Front 35

4. Motility Disorders

Back 35

1. Acute stress-related diarrhea.

2. Irritable bowel syndrome.

3. Post-vagotomy diarrhea.

4. Diabetic neuropathy diarrhea.

5. Thyrotoxic diarrhea.

6. Scleroderma.

Front 36

Motility Disorders
These disorders almost uniformly result in __________, and the ______________ is the most common cause of _____________ diagnosed by a gastroenterologist

Back 36

chronic diarrhea

irritable bowel syndrome

chronic diarrhea

Front 37

In the case of bowel failure and dilatation (such as in scleroderma bowel)

Mechanism:

Back 37

the basic mechanism is felt to be a rush of intestinal contents through the bowel with possibly some mismatch of foods with digestive chyme

Front 38

In the case of bowel stagnation on a motility basis the actual cause of diarrhea is:

Back 38

bacterial overgrowth occurs in the small intestine.

This bacterial overgrowth ultimately results in malabsorption and subsequent fatty acid diarrhea

Front 39

Deranged motility contributes to diarrhea in many diarrheal illnesses because of

Back 39

(1) Altered motor patterns due to fluid volume or

(2) Altered motor patterns from local inflammation, for example.

Front 40

Diarrhea Due to Brush Border or Enterocytic Damage/Death With Inflammation

(multiple mechanisms not just absorption/secretion problem alone)

Give 2 examples

Back 40

1) In celiac sprue there is malabsorption due to loss of villi and therefore absorptive surface, yet there is also a secretory component due to increased crypt secretory diarrhea.

2) Crohn's disease is a good example of a diarrheal illness characterized by enterocytic damage and inflammation which produce both malabsorption and secretion

Front 41

Duration of Diarrhea helps guide evaluation:

Acute vs. chronic

Compare Duration, Etiology, and general Course:

Back 41

Acute:
- Duration: <2-3 weeks
- Etiology: Infectious
- Course: Self-Limited

Chronic:
- Duration: > 3 weeks
- Etiology: Multiple
- Course: Variable

Front 42

History is helpful in evaluating patients with diarrhea:

History

Back 42

Duration, travel history, medications, patient age, diet

Front 43

History is helpful in evaluating patients with diarrhea

Character

Back 43

Frequency, volume, blood, consistency

* blood suggests inflammatory process

Front 44

History is helpful in evaluating patients with diarrhea

Other Manifestations

Back 44

Fever, weight loss, anorexia, nausea, vomiting, dehydration

Front 45

Site of involvement based on clinical presentation:

List common Small Bowel/Colonic Presentations (right sided)

Back 45

Small Bowel/Colonic Presentation
- Large Stool Volume
- Moderate increase in number of stools/day
- Minimal Urgency
- Little Mucus
- No Tenesmus

Tenesmus is a feeling of incomplete defecation. It is experienced as an inability or difficulty to empty the bowel at defecation. It is frequently painful and may be accompanied by involuntary straining and other gastrointestinal complications

Front 46

Site of involvement based on clinical presentation:

Recto-Sigmoidal Presentations: (Left-sided)

Back 46

- Small amount of stool
- Inc. Frequency (frequent tablespoon quantity)
- Inc. Urgency
- Tenesmus
- Mucus Blood

3) Rectal or lower left quadrant discomfort relieved by bowel movement

4) Discomfort improved by passing flatus.

5) Presence of bright red blood mixed in with the stool

6) The passage of mucus alone.

Front 47

Chronic and recurrent diarrhea should always be investigated

by:

Back 47

Stool exam:
- Cultures, ova and parasites
- Blood, leukocytes, microscopic fat
- Quantitative volumes and fat studies as indicated

Other studies
- Endoscopic examinations with biopsy
- Absorption studies
- Special studies:
- imaging studies (CAT scan, ultrasound, etc.)
- Barium studies
- Stool and urine analyses for laxative and diuretics

Front 48

The medications which commonly cause diarrhea include:

Back 48

antacids,
quinidine,
colchicine,
antibiotics,
laxatives,
diuretics,
glaucoma eye drops,
prostaglandins,
gold.

Front 49

Several approaches can be taken in the treatment of diarrhea

1. Specific (e.g. Lactose deficiency):

2. Non-specific (e.g. chronic idiopathic):

Back 49

1. Specific (e.g. Lactose deficiency):
- Cure underlying disease
- Correct pathophysiology

2. Non-specific (e.g. chronic idiopathic):
- Decrease net fluid secretions:
(decrease secretion, increase absorption)
- Modify motility:
(decrease propulsive contractions, increase mixing contractions)