Reyes, Maria Bernadette J.

August 23, 2013

1F2 Biochemistry
Clinical Case #3: DIARRHEA
1. Discuss the WHO definition of diarrhea. Discuss the different classifications of diarrhea based on the
following criteria and give examples.
a. Duration
b. Etiology
Diarrhoeal disease is the second leading cause of death in children under five years old, and
is responsible for killing around 760 000 children every year. Diarrhoea can last several days,
and can leave the body without the water and salts that are necessary for survival. Diarrhoea is
defined as the passage of three or more loose or liquid stools per day (or more frequent passage
than is normal for the individual). Diarrhoea is usually a symptom of an infection in the intestinal
tract, which can be caused by a variety of bacterial, viral and parasitic organisms. Infection is
spread through contaminated food or drinking-water, or from person-to-person as a result of poor
hygiene. Diarrhea lasting less than 2 weeks is considered acute diarrhea. The augmented water
content in the stools is due to an imbalance in the physiology of the small and large intestinal
processes involved in the absorption of ions, organic substrates, and thus water. This
phenomenon is most likely caused by an infectious agent, such as bacterial, parasitic or viral
invasion, or by a non-infectious agent such as dietary indiscretion or a new medication. Acute
diarrhea is typically self limiting and resolves quickly with no lasting sequelae. Infectious agents
are one of the factors associated with acute diarrhea. Some of these pathogens can cause an
inflammatory response in the gut where the epithelial lining is damaged either by a toxin
produced by the organism or by an organism invading the mucosa. Diarrhea lasting longer than
two weeks but resolving within a month is known as persistent diarrhea. This is typically a
slower to resolve infection or continuing use of an offending agent. Chronic diarrhea, on the
other hand, lasts longer than four weeks. Chronic diarrhea can be the result of disease processes,
medication, genetic abnormalities, or a variety of other causes.

2. Describe the mechanisms (and give some causes) of the different types of diarrhea.
a. Secretory diarrhea
b. Osmotic diarrhea
c. Inflammatory diarrhea
A. Large volumes of water are normally secreted into the small intestinal lumen, but a large
majority of this water is efficiently absorbed before reaching the large intestine. Diarrhea occurs
when secretion of water into the intestinal lumen exceeds absorption. Secretory diarrhea occurs
when there is an increase in the amount of fluid being drawn into the lumen of the bowel such that the
ability of the intestines to reabsorb is overwhelmed. It means that there is an increase in the active
secretion, or there is an inhibition of absorption. Either the gut is secreting more fluids than
usual, or it cannot absorb fluids properly. It occurs when the body is releasing water into the
bowel when it's not supposed to. Many infections, drugs, and other conditions cause secretory
diarrhea. This is most commonly caused by a cholera toxin, a protein secreted by the bacterium
Vibrio cholera, which strongly activates adenylyl cyclase, causing a prolonged increase in
intracellular concentration of cyclic AMP within crypt enterocytes. This change results in
prolonged opening of the chloride channels that are instrumental in secretion of water from the
crypts, allowing uncontrolled secretion of water. Therefore, to maintain a charge balance in the
lumen, sodium is carried with it, along with water. Additionally, cholera toxin affects the enteric
nervous system, resulting in an independent stimulus of secretion. In this type of diarrhea
intestinal fluid secretion is isotonic with plasma even during fasting. It continues even when
there is no oral food intake. In most cases, secretory diarrheas will not resolve during a 2-3 day
fast. There is little to no structural damage.
B. Absorption of water in the intestines is dependent on adequate absorption of solutes. If
excessive amounts of solutes are retained in the intestinal lumen, water will not be absorbed and
diarrhea will result. Osmotic diarrhea occurs when there is a dysfunction in the ability of the intestine
to reabsorb fluid as it flows through the lumen.It means that something in the bowel is drawing water
from the body into the bowel. This typically results from one of two situations- ingestion of a
poorly absorbed substrate or malabsorption of nutrients in the small intestine allowing a larger and
more liquid mass to enter the colon. This fecal matter then creates a negative osmotic gradient causing
leakage of more fluid into the gut increasing the stool volume. In ingestion of a poorly absorbed
substrate, the offending molecule is usually a carbohydrate or divalent ion. A common example
of this is "dietetic candy" or "chewing gum" diarrhea, in which a sugar substitute, such as
sorbitol, is not absorbed by the body but draws water from the body into the bowel, resulting in
diarrhea. Sugar alcohols such as sorbitol (often found in sugar-free foods) are difficult for the
body to absorb and, in large amounts, may lead to osmotic diarrhea. If a person drinks solutions
with excessive sugar or excessive salt, these can draw water from the body into the bowel and
too much water is drawn into the bowels. Osmotic diarrhea can also be the result of
maldigestion, in which the nutrients are left in the lumen to pull in water. A common example of
malabsorption is lactose intolerance resulting from a deficiency in the brush border enzyme
lactase. In such cases, a moderate quantity of lactose is consumed (usually as milk), but the
intestinal epithelium is deficient in lactase, and lactose cannot be effectively hydrolyzed into
glucose and galactose for absorption. The osmotically-active lactose is retained in the intestinal
lumen, where it "holds" water. A distinguishing feature of osmotic diarrhea is that it stops after
the patient is fasted or stops consuming the poorly absorbed solute.
C. Inflammatory diarrhea is when there is damage to the mucosal lining or brush border,
which leads to a passive loss of protein-rich fluids and a decreased ability to absorb these lost
fluids. Features of all three of the other types of diarrhea can be found in this type of diarrhea. It
can be caused by bacterial infections, viral infections, parasitic infections, or autoimmune
problems such as inflammatory bowel diseases. It can also be caused by tuberculosis, colon
cancer, and enteritis. The immune response to inflammatory conditions in the bowel contributes
substantively to development of diarrhea. Activation of WBC leads them to secrete inflammatory
mediators and cytokines which can stimulate secretion, in effect imposing a secretory component
on top of an inflammatory diarrhea. Reactive oxygen species from leukocytes can damage or kill
intestinal epithelial cells, which are replaced with immature cells that typically are deficient in
the brush border enyzmes and transporters necessary for absorption of nutrients and water. In this
way, components of an osmotic (malabsorption) diarrhea are added to the problem.

3. What is volume contraction? Describe the various types of volume contraction.

Volume contraction is a decrease in body fluid volume, also including any concomitant loss
of osmolytes. The loss of the water component of body fluid is specifically termed dehydration.
Volume contraction of extracellular fluid is directly coupled to and almost proportional to
volume contraction of blood plasma, which is termed hypovolemia. Thus, it primarily affects the
circulatory system, potentially causing hypovolemic shock. ECF volume contraction refers to a
decrease in ECF volume caused by sodium or water loss exceeding intake. Losses may be renal
or extrarenal through the gastrointestinal tract, skin, and lungs or by sequestration in potential
spaces in the body (e.g., abdomen, muscle) that are not in hemodynamic equilibrium with the
ECF. The reduction in ECF volume occurs simultaneously from both the interstitial and
intravascular compartments and is determined by whether the volume loss is primarily solute-
free water or a combination of sodium and water. The loss of solute-free water has a lesser effect
on intravascular volume because of the smaller amount of water present in the ECF compared
with the ICF and the free movement of water between fluid compartments. ECF volume
contraction or hypovolemia is usually the type of volume contraction of primary concern in
emergency, since ECF is approximately half the volume of ICF and is the first to be affected in
e.g. bleeding. Volume contraction of intracellular fluid may occur after substantial fluid loss,
since it is much larger than ECF volume, or loss of potassium (K+). ICF volume contraction may
cause disturbances in various organs throughout the body.

4. Discuss how to assess hydration status of individuals with diarrhea (based on WHO
classification). Assess the hydration status of the patient.
No Dehydration Mild Dehydration (>2 Severe Dehydration (>2 signs)
signs)
Alertness normal Restless or irritable Abnormally sleepy or
No sunken eyes Sunken eyes lethargic
Normal drinking Drinks eagerly Sunken eyes
Immediate skin Slow skin pinch (<2 Drinking poorly or not at
pinch sec) all
Very slow skin pinch (>2
sec)

Signs of dehydration in adults:

Pulse rate >90
Postural hypotension
Supine hypotension and absence of palpable pulse
Dry tongue
Sunken eyeballs
Skin pinch

5. What is the composition of oral rehydration solution recommended by WHO and rationale of
each composition.
Oral rehydration salts (ORS) solution is a mixture of clean water, salt and sugar. ORS is
absorbed in the small intestine and replaces the water and electrolytes lost in the feces. A basic
oral rehydration therapy solution is composed primarily of salt, sugar, and water using a standard
ratio: 30 ml sugar: 2.5 ml salt : 1 liter water; 2 tbl. sugar : 0.5 tsp. salt : 1 quart water. The
reduced osmolarity ORS has a total osmolarity of 245 mmol/L. Fluid from the body is normally
pumped into the intestinal lumen during digestion. This fluid is typically isosmotic with
bloodbecause it contains a high concentration of sodium (approx. 142 mEq/L). A healthy
individual will secrete 20-30 grams of sodium per day via intestinal secretions. Nearly all of this
is reabsorbed by the intestine, helping to maintain constant sodium levels in the body
(homeostasis). Because there is so much sodium secreted by the intestine, without intervention,
heavy continuous diarrhea can become a potentially life-threatening condition within hours. This
is because liquid secreted into the intestinal lumen during diarrhea passes through the gut so
quickly that little sodium is reabsorbed, leading to dangerously low sodium levels in the body
(severehyponatremia). This is the motivation for sodium and water replenishment via ORT.
Sodium absorption via the intestine occurs in two stages. The first is at the outermost cells
(intestinal epithelial cells) at the surface of the intestinal lumen. Sodium passes into these
outermost cells by co-transport via the SGLT1 protein. From there, sodium is pumped out of the
cells (basal side) and into the extracellular space by active transport via the sodium potassium
pump. The Na+/K+ ATPase pump on the basolateral membrane of the proximal tubule cell uses
ATP to move 3 sodium outward into the blood, while bringing in 2 potassium. This creates a
downhill sodium gradient inside the proximal tubule cell in comparison to both the blood and the
tubule. The SGLT proteins use the energy from this downhill sodium gradient created by the
ATPase pump to transport glucose across the apical membrane against an uphill glucose gradient.
Therefore, these co-transporters are an example of secondary active transport. (The GLUT
uniporters then transport the glucose across the basolateral membrane, into the peritubular
capillaries.) Both SGLT1 and SGLT2 are known as symporters, since both sodium and glucose
are transported in the same direction across the membrane. The co-transport of glucose into the
epithelial cells via the SGLT1 protein requires sodium. Two sodium ions and one molecule of
glucose/galactose are transported together across the cell membrane through the SGLT1 protein.
Without sodium present, intestinal glucose or galactose will not be absorbed. This is why ORSs
include both sodium and glucose. For each cycle of the transport, hundreds of water molecules
move into the epithelial cell, slowly rehydrating the affected individual.