3/15/2012

Aspek Biokimia Fungsi

Absorpsi dan Sekresi Intestinal
serta Hubungannya dengan
Patofisiologi Diare
Bagian Biokimia Kedokteran
Fakultas Kedokteran
Universitas Islam Sumatera Utara
2012

Normally, absorption and secretion of

water and electrolytes occur throughout
the intestine.
Water and electrolytes are simultaneously
absorbed by the villi and secreted by the
crypts of the bowel epithelium.
A healthy adult takes in less than 2 litres of
fluid each day. Saliva and secretions from
the stomach, pancreas, and liver add
about 7 litres, making a total of about
9 litres that enter the small intestine every
day.

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Only 100 to 200 mL of water being

excreted each day in formed stools.
When net secretion exceeds its limited
absorptive capacity, diarrhoea occurs.

When solutes (particularly sodium/Na) are

actively absorbed Osmotic gradients
are created Absorption of water from
the small intestine
To enter the epithelial cells, sodium is :
a. Linked to the absorption of chloride,
b. Absorbed directly as sodium ion,
c. Exchanged for hydrogen ion,
d. Linked to the absorption of organic
materials (monosaccharide, AA).

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Glucose
Galactose
Fructose

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After being absorbed, sodium is

transported out of the epithelial cells by
an ion pump referred to as Na+K+
ATPase Na to ECF Osmolality
Water and other electrolytes to flow
passively from the bowel lumen through
intercellular channels and into the ECF.

ECF : Extracellular fluid

ICF : Intracellular fluid
IS : Interstitial fluid

Secretory stimuli increase the ability of

chloride to pass through the luminal
membrane of the crypt cells, allowing that
ion to enter the bowel lumen
This movement of chloride ion creates an
osmotic gradient that causes water and
other electrolytes to flow passively from
the ECF into the bowel lumen through the
intercellular channels.

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SECRETION
cAMP, via Protein Kinase A (PKA), stimulates
secretion by activating or enhancing the
transport activities of three membrane proteins :
1. The apical anion channel.
cAMP opens the apical anion channel thereby
initiating secretion.
2. A basolateral membrane K+ channel.
The opening of a basolateral membrane K+
channel repolarizes the cell, sustaining the
electrical driving force for Cl extrusion into the
lumen.

3. A basolateral membrane NaK2Cl

cotransporter.
cAMP appears to enhance cotransporter
activity indirectly by opening the apical anion
channel and thereby decreasing cell [Cl],

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Compounds that stimulate active

secretion and inhibit active absorption:
a) Neurotransmitters:
Vasoactive intestinal peptide (VIP)
Acetylcholine
Substance P
ATP and UTP
b) Serotonin and Neurotensin.
Released by enterochromaffin cells
c) Prostaglandins, leukotrienes and plateletactivating factor (PAF).
Released by inflammatory cells.

(d)

Guanylin, a luminally active peptide

released by Goblet cells.

The Ca2+ increase opens a basolateral K+

channel different from that opened by
cAMP.
VIP and acetylcholine are the
predominant transmitters with direct
epithelial secretory and/or antiabsorptive
effects released by secreto-motor nerves.

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The group of compounds that both inhibit

active secretion (HCO3 as well as Cl) and
enhance active absorption, includes
norepinephrine (via 2-receptors),
neuropeptide Y, enkephalins, all
neurotransmitter, and somatostatin.
Norepinephrine, the predominant
antisecretory/proabsorptive agonist in the
intestines, activates 2-receptors on both
enterocytes (22) and nerves (S32, S33). The
neural effect is inhibitory, blocking release of
secretion-inducing neurotransmitters.

PATHOPHYSIOLOGY OF DIARRHEA
General Aspects
Patients may use the word diarrhea for
increases in stool mass (in adults, up to
250 g/dL is considered normal), stool
liquidity, or stool frequency. The first
criterion truly defines diarrhea.

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Diarrheal driving forces

Osmosis, active secretion, exudation,
and altered motility diarrhea.
Osmotic Diarrhea :
When poorly absorbable, lowmolecular
weight aqueous solutes are ingested, their
osmotic force quickly pulls water and,
secondarily, ions into the intestinal lumen.
Such as : Lactulose, sorbitol or Mg2+.

Osmotic diarrhea can also develop when an

ordinarily absorbable nutrient is ingested by an
individual with an absorptive defect.
Eg. Lactose intolerence congenital lactase
deficiency, or carbohydrate by someone with
gluten-sensitive enteropathy (celiac disease),
maldigestion in pancreatic insufficiency.

Secretory Diarrhea :
Diarrhea resulting from overstimulation of the
intestinal tracts secretory capacity can develop
in pure form (e.g., cholera) or as a component
of a more complex disease process (e.g., celiac
disease, Crohn disease).

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Pure secretory diarrhea is characterized by :

a.Large stool volumes (which can exceed 1 liter per
hour in well hydrated adults),
b.Absence of red or white blood cells in the stool,
c.Absence of fever or other systemic symptoms
(except those due to dehydration),
d.Persistence of diarrhea with fasting (volume may
diminish).
A number of secretory stimuli can cause
diarrhea, These include bacterial enterotoxins,
hormones generated by endocrine neoplasms,
dihydroxy bile acids, hydroxylated fatty acids, &
inflammatory mediators.

Exudative diarrhea :
If the intestinal epitheliums barrier function
is compromised by loss of epithelial cells or
disruption of tight junctions, hydrostatic pressure
in blood vessels & lymphatics will cause water
and electrolytes, mucus, protein, and sometimes
even red and white cells to accumulate luminally
(e.g., ulcerative colitis, shigellosis, intestinal
lymphangiectasia).

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PATOPHYSIOLOGY OF ACUTE
DIARRHEAS
Enteric infection with enterotoxin-producing
bacteria
Three bacterial enterotoxins produced by two
enteric organisms, V. cholerae and E. coli.
In fact, similar toxic peptides are produced by
Yersinia (S52), Salmonella (S53) and perhaps
other enteropathogenic bacteria,
The V. cholerae enterotoxin, is an 84-kDa
protein, consisting of a dimeric A subunit and
5 identical B subunits.

Toxigenic E. coli Travelers diarrhea

Elaborate at least two secretionstimulating enterotoxins : 1) Heat-labile
toxin and 2) Heat-stable toxin, activates
guanylate cyclase in the intestinal
epithelium , thereby activating cGMPdependent protein kinase (PKG), which,
like PKA, can open the CFTR anion
channel.

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Enterotoxin attach to endocrine

(enterochromaffin) cells on the villus
surface of the intestinal epithel, causing an
increase of cAMP or cGMP release
serotonin, neurotensin, and possibly other
peptides (eg. VIP) into the subepithelial
space.
The VIP attaches to receptors on both villus
and crypt enterocytes, activating adenylyl
cyclase and inducing cAMP-mediated
alterations of ion transport (inhibition of
absorption in villus cells and stimulation of
secretion in crypt cells).

Common bacterial causes of enteritis and/or

colitis are Shigella, Salmonella, Yersinia,
enteroinvasive E. coli, P. aeromonas, and
Campylobacter.
These organisms invade the epithelium and
multiply intracellularly, damaging the surface
epithelium and causing inflammation (release
inflamatory mediator ) Diarrhea.
Some viruses also invade the intestinal
epithelium, causing enterocyte destruction,
inflammation, and a temporary sprue-like
syndrome (partial villus atrophy and crypt
hypertrophy).

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These include rotavirus (worldwide, probably

the most common cause of diarrhea in
infants), certain adenoviruses.
Some enteric bacteria produce cytolytic
toxins that destroy epithelial cells, interfering
with absorption and causing inflammation.
These include : Shigella dysenteriae
(Shiga toxin), a protein synthesis inhibitor;
Clostridium difficile, (A toxin, alters
cytoskeletal structure), and whose
proliferation is induced by broad-spectrum
antibiotics; Vibrio parahaemolyticus.

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