Gastrointestinal Physiology

I. Structure and Innervation of the Gastrointestinal Tract

A. Structure of the gastrointestinal (GI) tract (Figure 6-1)

1* Epithelial cells

- are specialized in different parts of the GI tract for secretion or ab-
sorption*

2.  Muscularis mucosa

-Contraction causes a change in the surface area for secretion or ab-
sorption.

3.  Circular muscle

- Contraction causes a decrease in diameter of the lumen of the GI
tract.

4.  Longitudinal muscle

- Contraction causes shortening of a segment of the GI tract.

5.  Submucosal plexus (Meissner's plexus) and myenteric plexus

- comprise the enteric nervous system of the GI tract.

Figure 6-1. Structure of the gastrointestinal (Gi) tract.

- integrate and coordinate the motility, secretory, and endocrine functions
of the GI tract.

B. Innervation of the GI tract

- The autonomic nervous system (ANS) of the GI tract comprises both extrin-
sic and intrinsic nervous systems.

1.  Extrinsic innervation (parasympathetic and sympathetic ner-
vous systems)

- Efferent fibers carry information from the brain stem and spinal cord
to the GI tract.

-Afferent fibers carry sensory information from chemoreceptors and
mechanoreceptors in the GI tract to the brain stem and spinal cord.

a.  Parasympathetic nervous system

- is usually excitatory on the functions of the GI tract.

- is carried via the vagus and pelvic nerves.

- Preganglionic parasympathetic fibers synapse in the myenteric and
submucosal plexuses.

- Cell bodies in the ganglia of the plexuses then send information to
the smooth muscle, secretory cells, and endocrine cells of the GI tract.

(1)  The vagus nerve innervates the esophagus, stomach, pancreas,
and upper large intestine.

- Reflexes in which both afferent and efferent pathways are con-
tained in the vagus nerve are called vagovagal reflexes.

(2)   The pelvic nerve innervates the lower large intestine, rectum,
and anus.

b.  Sympathetic nervous system

- is usually inhibitory on the functions of the GI tract.

- Fibers originate in the spinal cord between T-8 and L-2.

- Preganglionic sympathetic cholinergic fibers synapse in the preverte-
bral ganglia.

- Postganglionic sympathetic adrenergic fibers leave the prevertebral
ganglia and synapse in the myenteric and submucosal plexuses. Direct
postganglionic adrenergic innervation of blood vessels and some
smooth muscle cells also occurs.

- Cell bodies in the ganglia of the plexuses then send information to
the smooth muscle, secretory cells, and endocrine cells of the GI tract.

2.  Intrinsic innervation (enteric nervous system)

- coordinates and relays information from the parasympathetic and sympa-
thetic nervous systems to the GI tract.

- uses local reflexes to relay information within the GI tract.

- controls most functions of the GI tract, especially motility and secretion,
even in the absence of extrinsic innervation.

a.  Myenteric plexus (Auerbach's plexus)

- primarily controls the motility of the GI smooth muscle.

b.   Submucosal plexus (Meissner's plexus)

- primarily controls secretion and blood flow.

- receives sensory information from chemoreceptors and mechanorecep-
tors in the GI tract.

Regulatory Substances in the Gastrointestinal Tract (Figure
6-2)

A. GI hormones (Table 6-1)

- are released from endocrine cells in the GI mucosa into the portal circulation,
enter the general circulation, and have physiologic actions on target cells.

- Four substances meet all of the requirements to be considered "official" GI
hormones; others are considered "candidate" hormones. The four official GI
hormones are gastrin, cholecystokinin (CCK), secretin, and gastric
inhibitory peptide (GIP).

L Gastrin

-contains 17 amino acids ("little gastrin")-

- Little gastrin is the form secreted in response to a meal.

- All of the biologic activity of gastrin resides in the four C-terminal
amino acids.

- "Big gastrin" contains 34 amino acids, although it is not a dimer of little
gastrin.

a. Actions of gastrin

(1)   Increases H⁴ secretion by the gastric parietal cells- Gastrin is

far more potent than histamine in stimulating gastric H⁴ secretion.

(2)   Stimulates growth of gastric mucosa and growth of mucosa
of the small intestine and colon by stimulating the synthesis of RNA
and new protein. Patients with gastrin-secreting tumors have
hypertrophy and hyperplasia of these tissues.

Figure 6-2. Gastrointestinal (GI) hormones, paracrines, and neurocrines.

Table 6-1. Summary of Gastrointestinal (GI) Hormones

CCK = cholecystokinin; GIP = gastric inhibitory peptide; GRP = gastrin-releasing peptide.

b.  Stimuli for secretion of gastrin

- Gastrin is secreted from the G cells of the gastric antrum in response
to a meal.

- Gastrin is secreted in response to the following:

(1)   Small peptides and amino acids in the lumen of the stomach

- The most potent stimuli for gastrin secretion are phenylalanine
and tryptophan.

(2)  Distention of the stomach

(3)  Vagal stimulation, mediated by gastrin-releasing peptide
(GRP)

- Atropine does not block vagally mediated gastrin secretion be-
cause the mediator of the vagal effect is GRP, not acetylcholine
(ACh).

c.  Inhibition of gastrin secretion

- H⁺ in the lumen of the stomach inhibits gastrin release. This
negative feedback control ensures that gastrin secretion is inhibited
if the stomach contents are sufficiently acidified.

d. Zollinger-Ellison syndrome

- occurs when gastrin is secreted by non-p-cell tumors of the pancreas.

2.   CCK

- contains 33 amino acids.

- is homologous to gastrin.

- The five C-terminal amino acids are the same in CCK and gastrin.

- The biologic activity of CCK resides in the C-terminal heptapeptide.

Thus, the heptapeptide contains the sequence that is homologous to gas-
trin and has gastrin activity as well as CCK activity.

a.  Actions of CCK

(1)   Stimulates contraction of the gallbladder and simultaneously
causes relaxation of the sphincter of Oddi for secretion of bile.

(2)   Stimulates pancreatic enzyme secretion.

(3)   Potentiates secretin-induced stimulation of pancreatic HC0₃~ se-
cretion.

(4)   Stimulates growth of the exocrine pancreas.

(5)   Inhibits gastric emptying. Thus, meals containing fat stimulate
the secretion of CCK, which slows gastric emptying to allow more
time for intestinal digestion and absorption.

b.   Stimuli for the release of CCK

- CCK is released from the I cells of the duodenal and jejunal
mucosa by:

(1)   Small peptides and amino acids

(2)   Fatty acids and monoglycerides

- Triglycerides do not stimulate the release of CCK because they
cannot cross intestinal cell membranes.

3.   Secretin

- contains 27 amino acids.

- is homologous to glucagon; fourteen of the twenty-seven amino acids
in secretin are the same as those in glucagon.

- All of the amino acids are required for biologic activity.

a.  Actions of secretin

- are coordinated to reduce the amount of H⁺ in the lumen of the small
intestine.

(1)   Stimulates pancreatic HC0₃" secretion and increases
growth of the exocrine pancreas. Pancreatic HC0₃~ neutralizes
H⁺ in the intestinal lumen.

(2)   Stimulates HCCV and H₂0 secretion by the liver, and increases
bile production.

(3)   Inhibits H⁺ secretion by gastric parietal cells.

b.  Stimuli for the release of secretin

- Secretin is released by the S cells of the duodenum in response to:

(1)  H⁺ in the lumen of the duodenum

(2)  Fatty acids in the lumen of the duodenum

4. GIP

- contains 42 amino acids.

- is homologous to secretin and glucagon.

a.  Actions of GIP

(1)   Stimulates insulin release. In the presence of an oral glucose
load, GIP causes the release of insulin from the pancreas. Thus,
an oral glucose load is more effective than intravenous
glucose in causing insulin release and, therefore, glucose utili-
zation.

(2)   Inhibits H⁺ secretion by gastric parietal cells (as is implied in
the name).

b.  Stimuli for the release of GIP

- GIP is secreted by the duodenum and jejunum.

- GIP is the only GI hormone that is released in response to fat, protein,
and carbohydrate. GIP secretion is stimulated by fatty acids, amino
acids, and orally administered glucose.

. Paracrines

- are released from endocrine cells in the GI mucosa.

- diffuse over short distances to act on target cells located in the GI tract.

- The GI paracrines are somatostatin and histamine.

1.   Somatostatin

-is secreted by cells throughout the GI tract in response to H⁺ in the
lumen. Its secretion is inhibited by vagal stimulation.

- inhibits the release of all GI hormones.

- inhibits gastric H⁺ secretion.

2.  Histamine

- is secreted by mast cells of the gastric mucosa.

- increases gastric H⁺ secretion directly and by potentiating the effects
of gastrin and vagal stimulation.

. Neurocrines

- are synthesized in neurons of the GI tract, moved by axonal transport down
the axon, and released by action potentials in the nerves.

- Neurocrines then diffuse across the synaptic cleft to a target cell.

-The GI neurocrines are vasoactive intestinal peptide (VIP), GRP
(bombesin), and enkephalins.

1.  VIP

- contains 28 amino acids and is homologous to secretin.

- is released from neurons in the mucosa and smooth muscle of the GI
tract.

-produces relaxation of GI smooth muscle.

- stimulates pancreatic HCCV secretion and inhibits gastric H⁺
secretion. In these actions, it resembles secretin.

- is secreted by pancreatic islet cell tumors and is presumed to mediate
pancreatic cholera.

2.   GRP (bombesin)

- is released from vagus nerves that innervate the G cells.

Figure 6-3. Gastrointestinal (GI) slow waves superimposed by action potentials. Action potentials produce
subsequent contraction.

- stimulates gastrin release from G cells.

3* Enkephalins (met-enkephalin and leu-enkephalin)

- are secreted from nerves in the mucosa and smooth muscle of the GI
tract.

- stimulate contraction of GI smooth muscle, particularly the lower
esophageal, pyloric, and ileocecal sphincters.

- inhibit intestinal secretion of fluid and electrolytes. This action forms
the basis for the usefulness of opiates in the treatment of diarrhea.

III. Gastrointestinal Motility

- Contractile tissue of the GI tract is almost exclusively unitary smooth muscle,
with the exception of the pharynx, upper one third of the esophagus, and external
anal sphincter, all of which are striated muscle*

- Depolarization of circular muscle leads to contraction of a ring of smooth
muscle and a decrease in diameter of that segment of the GI tract.

- Depolarization of longitudinal muscle leads to contraction in the longitudinal
direction and a decrease in length of that segment of the GI tract.

- Phasic contractions occur in the esophagus, gastric antrum, and small intes-
tine, which contract and relax periodically.

- Tonic contractions occur in the lower esophageal sphincter, orad stomach,
and ileocecal and internal anal sphincters.

A. Slow waves (Figure 6-3)

- are oscillating membrane potentials inherent to the smooth muscle
cells of some parts of the GI tract.

- are not action potentials, although they determine the pattern of
action potentials and, therefore, the pattern of contraction.

1. Mechanism of slow wave production

- is the cyclic activation and deactivation of the cell membrane Na⁺-K⁺
pump.

- Depolarization during each slow wave brings the membrane poten-
tial of smooth muscle cells closer to threshold and, therefore, increases
the probability that action potentials will occur.

- Action potentials, produced on top of the background of slow waves, then
initiate contraction of the smooth muscle cells (see Chapter 1 VII B).

2. Frequency of slow waves

- varies along the GI tract, but is constant and characteristic for each part
of the GI tract.

- is not influenced by neural or hormonal input. In contrast, the frequency
of action potentials is modified by neural and hormonal influences.

- sets the maximum frequency of contractions for each part of the
GI tract.

- is lowest in the stomach (3 slow waves/min) and highest in the
duodenum (12 slow waves/min).

B. Chewing, swallowing, and esophageal peristalsis

1.  Chewing

- lubricates food by mixing it with saliva.

- decreases the size of food particles to facilitate swallowing and to begin
the digestive process.

2.  Swallowing

- The swallowing reflex is coordinated in the medulla. Fibers in the
vagus and glossopharyngeal nerves carry information between the GI
tract and the medulla.

- The following sequence of events is involved in swallowing:

a.  The nasopharynx closes and, at the same time, breathing is inhibited.

b.  The laryngeal muscles contract to close the glottis and elevate the
larynx.

с Peristalsis begins in the pharynx to propel the food bolus toward
the esophagus. Simultaneously, the upper esophageal sphincter

relaxes to permit the food bolus to enter the esophagus.

3* Esophageal motility

- The esophagus propels the swallowed food into the stomach.

- Sphincters at either end of the esophagus prevent air from entering the
upper esophagus and gastric acid from entering the lower esophagus.

- The upper one third of the esophagus is striated muscle.

- Because the esophagus is located in the thorax, intraesophageal pressure
equals thoracic pressure, which is lower than atmospheric pressure.
In fact, a balloon catheter placed in the esophagus can be used to measure
intrathoracic pressure.

- The following sequence of events occurs as food moves into and down
the esophagus:

a.  As part of the swallowing reflex, the upper esophageal sphincter

relaxes to permit swallowed food to enter the esophagus.

b.  The upper esophageal sphincter then contracts so that food will not
reflux into the pharynx.

с A primary peristaltic contraction creates an area of high pressure
behind the food bolus. The peristaltic contraction moves down the esoph-
agus and propels the food bolus along. Gravity accelerates the
movement.

cL A secondary peristaltic contraction clears the esophagus of any
remaining food.

e.  As the food bolus approaches the lower end of the esophagus, the lower
esophageal sphincter relaxes. This relaxation is vagally mediated,
and the neurotransmitter is VIP.

f.  The orad region of the stomach relaxes ("receptive relaxation") to

allow the food bolus to enter the stomach.

4. Clinical correlations of esophageal motility

a.   Gastric reflux (heartburn) may occur if the tone of the lower esopha-
geal sphincter is decreased and gastric contents reflux into the
esophagus.

b.  Achalasia may occur if the lower esophageal sphincter does not relax
during swallowing and food accumulates in the esophagus.

С Gastric motility

- The stomach has three layers of smooth muscle—the usual longitudinal and
circular layers, and a third oblique layer.

- The stomach has three anatomic divisions—the fundus, body, and antrum.

- The orad region of the stomach includes the fundus and the proximal body.
This region contains oxyntic glands and is responsible for receiving the
ingested meal.

- The caudad region of the stomach includes the antrum and the distal body.
This region is responsible for the contractions that mix food and propel it
into the duodenum.

1.  "Receptive relaxation"

- is a vagovagal reflex that is initiated by distention of the stomach and
is abolished by vagotomy.

- The orad region of the stomach relaxes to accommodate the in-
gested meal.

- CCK participates in "receptive relaxation" by increasing the distensibil-
ity of the orad stomach.

2.  Mixing and digestion

- The caudad region of the stomach contracts to mix the food with gastric
secretions and begins the process of digestion. The size of food particles
is reduced.

a.   Slow waves in the caudad stomach occur at a frequency of 3-5 waves/
min. They depolarize the smooth muscle cells.

b.   If threshold is reached during the slow waves, action potentials are
fired, followed by contraction. Thus, the frequency of slow waves sets
the maximal frequency of contraction.

c.  A wave of contraction closes the distal antrum. Thus, as the caudad
stomach contracts, food is propelled back into the stomach to be mixed
(r etropulsion).

d.   Gastric contractions are increased by vagal stimulation and de-
creased by sympathetic stimulation.

e. Even during fasting, contractions (the "migrating myoelectric com-
plex") occur at 90-minute intervals and clear the stomach of residual
food. Motilin is the mediator of these contractions.

3. Gastric emptying

- The caudad region of the stomach contracts to propel food into the duo-
denum.

a.  The rate of gastric emptying is fastest if the stomach contents are
isotonic. If the stomach contents are hypertonic or hypotonic, gastric
emptying is slowed.

b.  Fat inhibits gastric emptying (i.e., increases gastric emptying time)
by stimulating the release of CCK.

c.  Н⁺ in the duodenum inhibits gastric emptying via direct neural
reflexes. H⁺ receptors in the duodenum relay information to the gastric
smooth muscle via interneurons in the GI plexuses.

D. Small intestinal motility

- The small intestine functions in the digestion and absorption of nutrients.
The small intestine mixes nutrients with digestive enzymes, exposes the
digested nutrients to the absorptive mucosa, and then propels any nonab-
sorbed material to the large intestine.

- As in the stomach, slow waves set the basic electrical rhythm, which occurs
at a frequency of 12 waves/min. Action potentials occur on top of the slow
waves and lead to contractions.

- Parasympathetic stimulation increases intestinal smooth muscle con-
traction; sympathetic stimulation decreases it.

1.   Segmentation contractions

- mix the intestinal contents.

- A section of small intestine contracts, sending the intestinal contents
(chyme) in both orad and caudad directions. That section of small intestine
then relaxes, and the contents move back into the segment.

- This back-and-forth movement produced by segmentation contrac-
tions causes mixing without any net forward movement of the chyme.

2.  Peristaltic contractions

- are highly coordinated and propel the chyme through the small intes-
tine toward the large intestine. Ideally, peristalsis occurs after digestion
and absorption have taken place.

- Contraction occurs behind the bolus and, simultaneously, relax-
ation occurs in front of the bolus, causing the chyme to be propelled
caudally.

- The peristaltic reflex is coordinated by the enteric nervous system.

3.  Gastroileal reflex

- is mediated by the extrinsic ANS and possibly by gastrin.

- The presence of food in the stomach triggers increased peristalsis in the
ileum and relaxation of the ileocecal sphincter. As a result, the intestinal
contents are delivered to the large intestine.

Б. Large intestinal motility

- Fecal material moves from the cecum to the colon (i.e., through the ascending,
transverse, descending, and sigmoid colons), to the rectum, and then to the
anal canal.

- Haustra, or sac-like segments, appear after contractions of the large in-
testine.

1.  Cecum and proximal colon

- When the proximal colon is distended with fecal material, the ileocecal
sphincter contracts to prevent reflux into the ileum.

a.  Segmentation contractions in the proximal colon mix the contents
and are responsible for the appearance of haustra.

b.  Mass movements occur 1 to 3 times/day and cause the colonic
contents to move distally for long distances (e.g., from the transverse
colon to the sigmoid colon).

2.  Distal colon

- Because most colonic water absorption occurs in the proximal colon, fecal
material in the distal colon becomes semisolid and moves slowly. Mass
movements propel it into the rectum.

3.  Rectum, anal canal, and defecation

- The sequence of events for defecation is as follows:

a.  As the rectum fills with fecal material, it contracts and the internal anal
sphincter relaxes (rectosphincteric reflex).

b.   Once the rectum is filled to about 25% of its capacity, there is an urge
to defecate. However, defecation is prevented because the external
anal sphincter is tonically contracted.

с When it is convenient to defecate, the external anal sphincter is
relaxed voluntarily. The smooth muscle of the rectum contracts, forcing
the feces out of the body.

- Intra-abdominal pressure is increased by expiring against a closed
glottis (Valsalva maneuver).

4.  Gastrocolic reflex

- The presence of food in the stomach increases the motility of the colon
and increases the frequency of mass movements.

a.  The gastrocolic reflex has a rapid parasympathetic component that
is initiated when the stomach is stretched by food.

b.  A slower, hormonal component is mediated by CCK and gastrin.

5.  Disorders of large intestinal motility

a.  Emotional factors strongly influence large intestinal motility via the
extrinsic ANS. Irritable bowel syndrome may occur during periods
of stress and may result in constipation (increased segmentation con-
tractions) or diarrhea (decreased segmentation contractions).

b.  Megacolon (Hirschsprung's disease), the absence of the co-
lonic enteric nervous system, results in constriction of the involved
segment, marked dilatation and accumulation of intestinal contents
proximal to the constriction, and severe constipation.

F. Vomiting

- A wave of reverse peristalsis begins in the small intestine, moving the GI
contents in the orad direction.

-The gastric contents are eventually pushed into the esophagus. If the upper
esophageal sphincter remains closed, retching occurs. If the pressure in
the esophagus becomes high enough to open the upper esophageal sphincter,
vomiting occurs.

- The vomiting center in the medulla is stimulated by tickling the back
of the throat, gastric distention, and vestibular stimulation (motion sickness).

- The chemoreceptor trigger zone in the fourth ventricle is activated
by emetics, radiation, and vestibular stimulation.

IV. Gastrointestinal Secretion (Table 6-2)

A. Salivary secretion
1. Functions of saliva

a.   Initial starch digestion by a-amylase (ptyalin) and initial triglyc-
eride digestion by lingual lipase

b.   Lubrication of ingested food by mucus

CCK = cholecystokinin; GIP = gastric inhibitory peptide.

с. Protection of the mouth and esophagus by dilution and buffering of
ingested foods

2.  Composition of saliva

a.  Saliva is characterized by:

(1)  High volume (relative to the small size of the salivary glands)

(2)  High K⁺ and HC0₃^- concentrations

(3)  Low Na⁺ and CI^- concentrations

(4)  Hypotonicity

(5)  Presence of a-amylase, lingual lipase, and kallikrein

b.  The composition of saliva varies with the salivary flow rate (Figure 6-4).

(1)  At the lowest flow rates, saliva has the lowest osmolarity and
lowest Na⁺ , CI^- , and HC0₃^- concentrations, but has the highest
K⁺ concentration.

(2)  At the highest flow rates (up to 4 ml/min), the composition of
saliva is closest to that of plasma.

3.  Formation of saliva (Figure 6-5)

- Saliva is formed by three major glands—the parotid, submaxillary,
and sublingual glands.

Figure 6-4. Composition of saliva as a function of salivary flow rate.

Figure 6-5. Modification of saliva by ductal cells.

- The structure of each gland is similar to a bunch of grapes. The acinus
(the blind end of each duct) is lined with acinar cells and secretes an
initial saliva. A branching duct system is lined with columnar epithelial
cells, which modify the initial saliva.

- When saliva production is stimulated, myoepithelial cells that line the
acinus and initial ducts contract and eject saliva into the mouth.

a.  The acinus

- produces an initial saliva with a composition similar to plasma.

- This initial saliva is isotonic and has the same Na⁺, K⁺, CI^-, and HC0₃^-
concentrations as plasma.

b.  The ducts

- modify the initial saliva by the following processes:

(1)  The ducts reabsorb Na⁺ and CI^-; therefore, the concentrations
of these ions are lower than their plasma concentrations.

(2)   The ducts secrete K⁺ and HC0₃^-; therefore, the concentrations
of these ions are higher than their plasma concentrations.

(3)  Aldosterone acts on the ductal cells to increase the reabsorption
of Na⁺ and the secretion of K⁺ (analogous to its actions on the renal
distal tubule).

(4)   Saliva becomes hypotonic in the ducts because the ducts are
relatively impermeable to water. Because more solute than water
is reabsorbed by the ducts, the saliva becomes dilute relative to
plasma.

(5)   The effect of flow rate on saliva composition is explained by
changes in the contact time available for reabsorption and secretion
processes to occur in the ducts.

- Thus, at high flow rates, saliva is most like the initial secretion
from the acinus; it has the highest Na⁺ and Cl^- concentrations
and the lowest K⁺ concentration.

- At low flow rates, saliva is least like the initial secretion from
the acinus; it has the lowest Na⁺ and CI^- concentrations and the
highest K⁺ concentration.

-The only ion that does not "fit" this contact-time explanation
is HC(V; HC0₃^- secretion is selectively stimulated when saliva
secretion is stimulated.

4. Regulation of saliva production (Figure 6-6)

- Saliva production is controlled by the parasympathetic and sympathetic
nervous systems (not by GI hormones).

- Saliva production is unique in that it is increased by both parasympa-
thetic and sympathetic activity. Parasympathetic activity is more
important, however.

a. Parasympathetic stimulation (cranial nerves VII and IX)

- increases saliva production by increasing transport processes in
the acinar and ductal cells and by causing vasodilation.

- Cholinergic receptors on acinar and ductal cells are muscarinic.

Figure 6-6. Regulation of salivary secretion. ACh = acetylcholine; cAMP = cyclic adenosine monophosphate;
IP₃ = inositol 1,4,5-triphosphate; NE = norepinephrine.

-The second messenger is inositol 1,4,5-triphosphate (IP₃) and
increased intracellular [Ca²⁺].

- Anticholinergic drugs (e.g., atropine) inhibit the production of saliva
and cause dry mouth.

b. Sympathetic stimulation

- increases the production of saliva and the growth of salivary
glands, although the effects are smaller than those of parasympathetic
stimulation.

- Receptors on acinar and ductal cells are p-adrenergic.

-The second messenger is cyclic adenosine monophosphate
(cAMP).

с Saliva production

- is increased (via activation of the parasympathetic nervous system)
by food in the mouth, smells, conditioned reflexes, and nausea.

- is decreased (via inhibition of the parasympathetic nervous system)
by sleep, dehydration, fear, and anticholinergic drugs.

B. Gastric secretion

1. Gastric cell types and their secretions (Table 6-3 and Figure 6-7)

Table 6-3. Gastric Cell Types and Their Secretions

Cell Type

Parietal cells

Chief cells

G cells

Mucous cells

Part of Stomach

Body (fundus)

Body (fundus)

Antrum

Antrum

Secretion Products

HC1

Intrinsic factor
(essential)

Pepsinogen
(converted to pepsin
at low pH)

Gastrin

Mucus
Pepsinogen

Stimulus for Secretion

Gastrin

Vagal stimulation (ACh)

Histamine

Vagal stimulation (ACh)

Vagal stimulation (via
GRP)

Small peptides

Inhibited by somatostatin

Inhibited by H⁺ in
stomach (via stimulation
of somatostatin release)

Vagal stimulation (ACh)

ACh = acetylcholine; GRP = gastrin-releasing peptide.

Fundus

G cells

Body

Gastrin - -

Antrum

Figure 6-7. Gastric cell types and their functions.

- Parietal cells, located in the body, secrete HC1 and intrinsic factor,

- Chief cells, located in the body, secrete pepsinogen.

- G cells, located in the antrum, secrete gastrin.

2.  Mechanism of gastric H⁺ secretion (Figure 6-8)

- Parietal cells secrete HC1 into the lumen of the stomach and, con-
currently, absorb HC0₃" into the bloodstream as follows:

a.  In the parietal cells, C0₂ and H₂0 are converted to H⁺ and HC0₃~,
catalyzed by carbonic anhydrase.

b.  H⁺ is secreted into the lumen of the stomach by the H⁺-K⁺ pump
(H⁺,K⁺-ATPase). Cl~ is secreted along with H⁺; thus, the secretion
product of the parietal cells is HCL

- The drug omeprazole inhibits the H⁺,K⁺-ATPase and blocks H⁺ se-
cretion.

с The HCO3" produced in the cells is absorbed into the bloodstream in
exchange for CI" (C1"-HC0₃" exchange). As HC0₃~ is added to the
venous blood, the pH of the blood increases ("alkaline tide"). (Eventu-
ally, this HCO3" will be secreted in pancreatic secretions to neutralize
H⁺ in the small intestine.)

- If vomiting occurs, gastric H⁺ never arrives in the small intestine,
there is no stimulus for pancreatic HC0₃" secretion, and the arterial
blood becomes alkaline (metabolic alkalosis).

3.   Stimulation of gastric H⁺ secretion (Figure 6-9)

a. Vagal stimulation

- increases H⁺ secretion by a direct pathway and an indirect pathway.

- In the direct path, the vagus nerve innervates parietal cells
and stimulates H⁺ secretion directly. The neurotransmitter at these
synapses is ACh, the receptor on the parietal cells is muscarinic, and
the second messenger is IP₃ and increased intracellular [Ca²⁺].

- In the indirect path, the vagus nerve innervates G cells and
stimulates gastrin secretion, which then stimulates H⁺ secretion by
an endocrine action. The neurotransmitter at these synapses is GRP
(not ACh).

Figure 6-8. Simplified mechanism of H⁺ secretion by gastric parietal cells.

Figure 6-9. Agents and second messengers that stimulate H⁺ secretion in gastric parietal cells. ACh = acetylcho-
line; cAMP = cyclic adenosine monophosphate; IP₃ = inositol 1,4,5-triphosphate.

- Atropine, a cholinergic muscarinic antagonist, inhibits H⁺ secretion
by blocking the direct pathway, which uses ACh as a neurotransmitter.
However, atropine does not block H⁺ secretion completely because it
does not inhibit the indirect pathway, which uses GRP as a neurotrans-
mitter.

- Vagotomy eliminates both pathways.

b. Histamine

- is released from mast cells in the gastric mucosa and diffuses to the
nearby parietal cells.

- stimulates H⁺ secretion by activating H₂ receptors on the parietal
cell membrane.

- The second messenger for histamine is cAMP.

- H₂ receptor-blocking drugs, such as cimetidine, inhibit H⁺ secretion
by blocking the stimulatory effect of histamine.

с Gastrin

- is released in response to eating a meal (small peptides, distention of
the stomach, vagal stimulation).

- stimulates H⁺ secretion by interacting with an unidentified receptor
on the parietal cells.

- The second messenger for gastrin on the parietal cell has not been
identified, but is clearly different from those for ACh and histamine
because their actions are additive with those of gastrin.

d. Potentiating effects of ACh, histamine, and gastrin on H⁺ se-
cretion

- Potentiation occurs when the response to simultaneous administra-
tion of two stimulants is greater than the sum of responses to either
agent given alone. As a result, low concentrations of stimulants given
together can produce maximal effects.

- Potentiation of gastric H⁺ secretion can be explained, in part, because
each agent has a different mechanism of action on the pari-
etal cell.

(1)  Histamine potentiates the actions of ACh and gastrin in

stimulating H⁺ secretion.

- Thus, H₂ receptor blockers (e.g., cimetidine) are particularly
effective in treating ulcers because they block both the direct
action of histamine on parietal cells and the potentiating effects
of histamine on ACh and gastrin.

(2)  ACh potentiates the actions of histamine and gastrin in
stimulating H⁺ secretion.

- Thus, muscarinic receptor blockers, such as atropine, block both
the direct action of ACh on parietal cells and the potentiating
effects of ACh on histamine and gastrin.

4.  Inhibition of gastric H⁺ secretion

- Negative feedback mechanisms inhibit the secretion of H⁺ by the pari-
etal cells.

a.  Low pH (< 3.0) in the stomach

- inhibits gastrin secretion and thereby inhibits H⁺ secretion.

- After a meal is ingested, H⁺ secretion is stimulated by the mechanisms
discussed previously (see IV В 2). After the meal is digested and the
stomach emptied, further H⁺ secretion decreases the pH of the stom-
ach contents. When the pH of the stomach contents is < 3.0, gastrin
secretion is inhibited and, by negative feedback, further H⁺ secretion
is inhibited.

b.   Chyme in the duodenum

- inhibits H⁺ secretion both directly and via hormonal mediators.

- The hormonal mediators are GIP (released by fatty acids in the duode-
num) and secretin (released by H⁺ in the duodenum).

5.  Pathophysiology of gastric H⁺ secretion

a* Gastric ulcers

- If the normal protective barrier of the stomach is damaged, the pres-
ence of H⁺ and pepsin may injure the gastric mucosa.

- H⁺ secretion is decreased, not increased (as might be assumed).

- Gastrin levels are increased (by negative feedback) in patients
with gastric ulcer disease because of lower-than-normal H⁺ secretion.

b.  Duodenal ulcers

- are more common than gastric ulcers.

- H⁺ secretion is higher than normal and is responsible, along with
pepsin, for damaging the duodenal mucosa.

- Gastrin levels in response to a meal are higher than normal*

- Parietal cell mass is increased because of the trophic effect of
gastrin.

c.  Zollinger-Ellison syndrome

- occurs when a gastrin-secreting tumor of the pancreas causes
increased H⁺ secretion.

с.

- Н⁺ secretion continues unabated because the gastrin secreted by pan-
creatic tumor cells is not subject to negative feedback inhibition by H⁺.

6. Drugs that block H⁺ secretion are used in the treatment of ulcers

(see Figure 6-9).

a.  Atropine

- blocks H⁺ secretion by inhibiting cholinergic muscarinic receptors on
parietal cells, thereby inhibiting ACh stimulation of H⁺ secretion.

b.  Cimetidine

- blocks H₂ receptors and thereby inhibits histamine stimulation of H⁺
secretion.

- is particularly effective in reducing H⁺ secretion because it not only
blocks the histamine stimulation of H⁺ secretion, but also blocks hista-
mine's potentiation of ACh effects.

c.  Omeprazole

- directly inhibits H⁺,K⁺-ATPase and H⁺ secretion.

Pancreatic secretion

- contains a high concentration of HC0₃ , whose purpose is to neutralize the

acidic chyme that reaches the duodenum,
-contains enzymes essential for the digestion of protein, carbohydrate,

and fat.

1. Composition of pancreatic secretion

a.  Pancreatic juice is characterized by:

(1)   High volume

(2)   Virtually the same Na⁺ and K⁺ concentrations as plasma

(3)   Much higher HC0₃~ concentration than plasma

(4)   Much lower CI" concentration than plasma

(5)   Isotonicity

(6)  Pancreatic lipase, amylase, and proteases

b.  The composition of the aqueous component of pancreatic secretion varies
with the flow rate (Figure 6-10).

Figure 6-10. Composition of pancreatic secretion as a function of pancreatic flow rate.

-At low flow rates, the pancreas secretes an isotonic fluid that is
composed mainly of Na⁺ and СГ.

- At high flow rates, the pancreas secretes an isotonic fluid that is
composed mainly of Na⁺ and HC0₃~.

- Regardless of the flow rate, pancreatic secretions are isotonic.

2,  Formation of pancreatic secretion (Figure 6-11)

- Like the salivary glands, the exocrine pancreas resembles a bunch of
grapes.

- The acinar cells of the exocrine pancreas make up most of its weight.

a.  Acinar cells

- produce a small volume of initial pancreatic secretion, which is mainly
Na⁺ and CI".

b.  Ductal cells

- modify the initial pancreatic secretion by secreting HC0₃" and ab-
sorbing CI" via a C1"-HC0₃~ exchange mechanism in the luminal
membrane.

- Because the pancreatic ducts are permeable to water, H₂0 moves
into the lumen to make the pancreatic secretion isosmotic.

3.  Regulation of pancreatic secretion

a.  Secretin

- is secreted by the S cells of the duodenum in response to H⁺ in the
duodenal lumen.

- acts on the pancreatic ductal cells to increase HC0₃~ secretion.

- Thus, when H⁺ is delivered from the stomach to the duodenum, secretin
is released. As a result, HC0₃~ is secreted from the pancreas into the
duodenal lumen to neutralize the H⁺.

- The second messenger for secretin is cAMP.

b.  CCK

- is secreted by the I cells of the duodenum in response to small peptides,
amino acids, and fatty acids in the duodenal lumen.

- acts on the pancreatic acinar cells to increase enzyme secre-
tion (amylase, lipases, proteases).

Figure 6-11. Modification of pancreatic secretion by ductal cells.

- potentiates the effect of secretin on ductal cells to stimulate HC0₃~
secretion.

- The second messenger for CCK is IP₃ and increased intracellular
[Ca²⁺]. The potentiating effects of CCK on secretin are explained by
the different mechanisms of action for the two GI hormones (i.e.,
cAMP for secretin and 1Рз/Са²⁺ for CCK).

c. ACh (via vagovagal reflexes)

- is released in response to H⁺, small peptides, amino acids, and fatty
acids in the duodenal lumen.

- stimulates enzyme secretion by the acinar cells and, like CCK,
potentiates the effect of secretin on HC0₃" secretion.

4. Cystic fibrosis

- is a disorder of pancreatic secretion.

- results from a defect in CI" channels that is caused by a mutation in the
cystic fibrosis transmembrane conductance regulator (CFTR)
gene.

- is associated with a deficiency of pancreatic enzymes resulting in
malabsorption and steatorrhea.

D. Bile secretion and gallbladder function (Figure 6-12)

1. Composition and function of bile

- Bile contains bile salts, phospholipids, cholesterol, and bile pigments
(bilirubin).

a* Bile salts

- are amphipathic molecules because they have both hydrophilic and
hydrophobic portions. In aqueous solution, bile salts orient themselves
around droplets of lipid and keep the lipid droplets dispersed (emul-
sified).

Figure 6-12. Recirculation of bile acids from the ileum to the liver. CCK = cholecystokinin.

- aid in the intestinal digestion and absorption of lipids by emulsifying
and solubilizing them in micelles.

b. Micelles

- Above a critical micellar concentration, bile salts form micelles.

- Bile salts are positioned on the outside of the micelle, with their
hydrophilic portions dissolved in the aqueous solution of the intestinal
lumen and their hydrophobic portions dissolved in the micelle interior,

- Free fatty acids and monoglycerides are present in the inside of the
micelle, essentially "solubilized" for subsequent absorption.

2.  Formation of bile

- Bile is produced continuously by hepatocytes.

- Bile drains into the hepatic ducts and is stored in the gallbladder for
subsequent release.

- Choleretic agents increase the formation of bile.

- Bile is formed by the following process:

a.  Primary bile acids (cholic acid and chenodeoxycholic acid) are

synthesized from cholesterol by hepatocytes.

- In the intestine, bacteria convert a portion of each of the primary bile
acids to secondary bile acids (deoxycholic acid and lithocholic
acid).

- Synthesis of new bile acids occurs, as needed, to replace bile acids
that are excreted in the feces.

b.  The bile acids are conjugated with glycine or taurine to form their
respective bile salts, which are named for the parent bile acid (e.g.,
taurocholic acid is cholic acid conjugated with taurine).

с Electrolytes and H₂0 are added to the bile.

d.  During the interdigestive period, the gallbladder is relaxed, the sphinc-
ter of Oddi is closed, and the gallbladder fills with bile.

e.  Bile is concentrated in the gallbladder as a result of isosmotic reab-
sorption of solutes and H₂0.

3.   Contraction of the gallbladder

a.   CCK

- is released in response to small peptides and fatty acids in the
duodenum.

- tells the gallbladder that bile is needed to emulsify and absorb lipids
in the duodenum.

- causes contraction of the gallbladder and relaxation of the
sphincter of Oddi.

b.  ACh

- causes contraction of the gallbladder.

4.  Recirculation of bile acids to the liver

- The terminal ileum contains a Na⁺-bile acid cotransporter, which is a
secondary active transporter that recirculates bile acids to the liver.

- Because bile acids are not recirculated to the liver until they reach the
terminal ileum, bile acids are present for maximal absorption of lipids
throughout the upper small intestine.

- After ileal resection, bile acids are not recirculated to the liver, but
are excreted in feces. The bile acid pool is thereby depleted and fat
absorption is impaired, resulting in steatorrhea.

V. Digestion and Absorption (Table 6-4)

- Carbohydrates, protein, and lipids are digested and absorbed in the small in-
testine.

- The surface area for absorption in the small intestine is greatly increased by
the presence of the brush border.

A. Carbohydrates

1. Digestion of carbohydrates

- Only monosaccharides are absorbed. Carbohydrates must be di-
gested to glucose, galactose, and fructose for absorption to proceed.

Table 6-4. Summary of Digestion and Absorption

a.  a-Amylases (salivary and pancreatic) hydrolyze 1,4-glycosidic bonds
in starch, yielding maltose, maltotriose, and a-limit dextrins.

b.  Maltase, a-dextrinase, and sucrase in the intestinal brush border
then hydrolyze the oligosaccharides to glucose.

c.   Lactase, trehalase, and sucrase degrade their respective disaccharides
to monosaccharides.

- Lactase degrades lactose to glucose and galactose.

- Trehalase degrades trehalose to glucose.

- Sucrase degrades sucrose to glucose and fructose.

2.  Absorption of carbohydrates (Figure 6-13)

a.  Glucose and galactose

- are transported from the intestinal lumen into the cells by Na⁺-depen-
dent cotransport in the luminal membrane. The sugar is transported
"uphill" and Na⁺ is transported "downhill."

- are then transported from cell to blood by facilitated diffusion.

- The Na⁺-K⁺ pump in the basolateral membrane keeps the intracellular
[Na⁺] low, thus maintaining the Na⁺ gradient across the luminal mem-
brane.

- Poisoning the Na⁺-K⁺ pump inhibits glucose and galactose absorption
by dissipating the Na⁺ gradient.

b.  Fructose

- is transported exclusively by facilitated diffusion; therefore, it cannot
be absorbed against a concentration gradient.

3.  Clinical disorders of carbohydrate absorption

- Lactose intolerance results from the absence of brush border lactase
and, thus, the inability to hydrolyze lactose to glucose and galactose for
absorption. Nonabsorbed lactose and H₂0 remain in the lumen of the GI
tract and cause osmotic diarrhea.

B. Protein

1. Digestion of proteins

Figure 6-13. Mechanism of absorption of monosaccharides by intestinal epithelial cells. Glucose and galactose
are absorbed by Na⁺-dependent cotransport (secondary active), and fructose (not shown) is absorbed by facilitated
diffusion.

a.  Endopeptidases

- degrade proteins by hydrolyzing interior peptide bonds.

b.  Exopeptidases

- hydrolyze one amino acid at a time from the С terminus of proteins
and peptides.

с Pepsin

- is not essential for protein digestion.

- is secreted as pepsinogen by the chief cells of the stomach.

- Pepsinogen is activated to pepsin by gastric H⁺.

- The optimum pH for pepsin is between 1 and 3.

- When the pH is > 5, pepsin is denatured. Thus, in the intestine, as
HC0₃" is secreted in pancreatic fluids, duodenal pH increases and
pepsin is inactivated.

d. Pancreatic proteases

- include trypsin, chymotrypsin, elastase, carboxypeptidase A, and car-
boxypeptidase B.

- are secreted in inactive forms that are activated in the small intestine
as follows:

(1)  Trypsinogen is activated to trypsin by a brush border enzyme,
enterokinase.

(2)  Trypsin then converts chymotrypsinogen, proelastase, and procar-
boxypeptidase A and В to their active forms. (Even trypsinogen
is converted to more trypsin by trypsin!)

(3)  After their digestive work is complete, the pancreatic proteases
degrade each other and are absorbed along with dietary proteins.

2. Absorption of proteins (Figure 6-14)

- Digestive products of protein can be absorbed as amino acids, dipep-
tides, and tripeptides (in contrast to carbohydrates, which can only
be absorbed as monosaccharides).

a. Absorption of free amino acids

- Na⁺-dependent amino cotransport occurs in the luminal mem-
brane. It is analogous to the cotransporter for glucose and galactose.

Figure 6-14. Mechanism of absorption of amino acids, dipeptides, and tripeptides by intestinal epithelial cells.
Each is absorbed by Na⁺-dependent cotransport.

- The amino acids are then transported from cell to blood by facilitated
diffusion.

-There are four separate carriers for neutral, acidic, basic, and
imino amino acids, respectively.

b. Absorption of dipeptides and tripeptides

- is faster than absorption of free amino acids.

- Na⁺-dependent cotransport of dipeptides and tripeptides also
occurs in the luminal membrane.

- After the dipeptides and tripeptides are transported into the intestinal
cells, cytoplasmic peptidases hydrolyze them to amino acids.

- The amino acids are then transported from cell to blood by facilitated
diffusion.

С Lipids

1.  Digestion of lipids

a.  Stomach

(1)   In the stomach, mixing breaks lipids into droplets to increase the
surface area for digestion by pancreatic enzymes.

(2)  Lingual lipases digest some of the ingested triglycerides to mono-
glycerides and fatty acids. However, most of the ingested lipids are
digested in the intestine by pancreatic lipases.

(3)   CCK slows gastric emptying. Thus, delivery of lipids from the
stomach to the duodenum is slowed to allow adequate time for
digestion and absorption in the intestine.

b.   Small intestine

(1)  Bile acids emulsify lipids in the small intestine, increasing the
surface area for digestion.

(2)  Pancreatic lipases hydrolyze lipids to fatty acids, monoglycer-
ides, cholesterol, and lysolecithin. The enzymes are pancreatic li-
pase, cholesterol ester hydrolase, and phospholipase A₂.

(3)  The hydrophobic products of lipid digestion are solubilized in mi-
celles by bile acids.

2.  Absorption of lipids

a.  Micelles bring the products of lipid digestion into contact with the
absorptive surface of the intestinal cells. Then, fatty acids, monoglyc-
erides, and cholesterol diffuse across the luminal membrane
into the cells. Glycerol is hydrophilic and is not contained in the
micelles.

b.   In the intestinal cells, the products of lipid digestion are reesterified to
triglycerides, cholesterol ester, and phospholipids and, with apoproteins,
form chylomicrons.

- Lack of apoprotein В results in the inability to transport chylomicrons
out of the intestinal cells and causes abetalipoproteinemia.

c.  Chylomicrons are transported out of the intestinal cells by exocytosis.
Because chylomicrons are too large to enter the capillaries, they are
transferred to lymph vessels and are added to the bloodstream via
the thoracic duct.

3, Malabsorption of lipids—steatorrhea

- can be caused by any of the following:

a.  Pancreatic disease (e.g., pancreatitis, cystic fibrosis), in which the
pancreas cannot synthesize adequate amounts of the enzymes needed
for lipid digestion

b.  Hypersecretion of gastrin, in which gastric H⁺ secretion is increased
and the duodenal pH is decreased. Low duodenal pH inactivates pancre-
atic lipase.

с Ileal resection, which leads to a depletion of the bile acid pool because
the bile acids do not recirculate to the liver

d.  Bacterial overgrowth, which may lead to deconjugation of bile acids
and their "early" absorption in the upper small intestine. In this case,
bile acids are not present throughout the small intestine to aid in lipid
absorption.

e.  Decreased number of intestinal cells for lipid absorption (tropical
sprue)

f.  Failure to synthesize apoprotein B, which leads to the inability to
form chylomicrons

D. Absorption and secretion of electrolytes and H₂0

- Electrolytes and H₂0 may cross intestinal epithelial cells by either cellular
or paracellular (between cells) routes.

- Tight junctions attach the epithelial cells to one another at the luminal
membrane.

- The permeability of the tight junctions varies with the type of epithelium.
A "tight" (impermeable) epithelium is the colon. "Leaky" (permeable)
epithelia are the small intestine and gallbladder.

1. Absorption of NaCl

a. Na⁺ moves into the intestinal cells, across the luminal membrane, and
down its electrochemical gradient by the following mechanisms:

(1)  Passive diffusion (through Na⁺ channels)

(2)  Na⁺-glucose or Na⁺-amino acid cotransport

(3)   Na⁺-Cl" cotransport

(4)  Na⁺-H⁺ exchange

-in the small intestine, Na⁺-glucose cotransport, Na⁺-amino acid
cotransport, and Na⁺-H⁺ exchange mechanisms are most important.
These cotransport and exchange mechanisms are similar to those in
the renal proximal tubule.

- In the colon, passive diffusion via Na⁺ channels is most important.
The Na⁺ channels of the colon are similar to those in the renal distal
tubule and are stimulated by aldosterone.

b.   Na⁺ is pumped out of the cell against its electrochemical gradient by
the Na⁺-K⁺ pump in the basolateral membranes.

c.   CI absorption accompanies Na⁺ absorption throughout the GI tract by
the following mechanisms:

(1)  Passive diffusion by a paracellular route

(2)   Na⁺-Cl" cotransport

(3)   CI--HCO3-exchange

2.  Absorption and secretion of K⁺

a.   Dietary K⁺ is absorbed in the small intestine by passive diffusion
via a paracellular route.

b.  K⁺ is actively secreted in the colon by a mechanism similar to that
for K⁺ secretion in the renal distal tubule.

-As in the distal tubule, K⁺ secretion in the colon is stimulated by
aldosterone.

- In diarrhea, K⁺ secretion by the colon is increased because of a flow
rate-dependent mechanism similar to that in the renal distal tubule.
Excessive loss of K⁺ in diarrheal fluid causes hypokalemia.

3.  Absorption of H₂0

- is secondary to solute absorption.

- is isosmotic in the small intestine and gallbladder. The mechanism
for coupling solute and water absorption in these epithelia is the same
as that in the renal proximal tubule.

- In the colon, H₂0 permeability is much lower than in the small intestine,
and feces may be hypertonic.

4.   Secretion of electrolytes and H₂0 by the intestine

- The GI tract also secretes electrolytes from blood to lumen.

-The secretory mechanisms are located in the crypts. The absorptive
mechanisms are located in the villi.

a.  CI" is the primary ion secreted into the intestinal lumen. It is
transported through CI" channels in the luminal membrane that are
regulated by cAMP.

b.   Na⁺ is secreted into the lumen by passively following CI". H₂0 follows
NaCl to maintain isosmotic conditions.

с Vibrio cholerae (cholera toxin) causes diarrhea by stimulating CI"
secretion.

- Cholera toxin binds to receptors in the luminal membrane of crypt
cells and activates adenylate cyclase in the basolateral membrane.

- Intracellular cAMP increases; as a result, CI" channels in the luminal
membrane open.

- Na⁺ and H₂0 follow CI" into the lumen and lead to secretory di-
arrhea.

- Some strains of Escherichia coli cause diarrhea by a similar mech-
anism.

E. Absorption of other substances
1. Vitamins

a.  Fat-soluble vitamins (A, D, E, and K) are incorporated into micelles
and absorbed along with other lipids.

b.  Most water-soluble vitamins are absorbed by Na⁺-dependent co-
transport mechanisms.

c.  Vitamin B₁₂ is absorbed in the ileum and requires intrinsic
factor.

- The vitamin B₁₂-intrinsic factor complex binds to a receptor on the
ileal cells and is absorbed.

- Gastrectomy results in the loss of gastric parietal cells as the source
of intrinsic factor. Injection of vitamin Bi₂ is required to prevent perni-
cious anemia.

2.   Calcium

- absorption in the small intestine depends on the presence of adequate
amounts of the active form of vitamin D, 1,25-dihydroxycholecalcif-
erol, which is produced in the kidney.

- Vitamin D deficiency or chronic renal failure results in inadequate intesti-
nal Ca²⁺ absorption, causing rickets in children and osteomalacia in
adults.

3.  Iron

- is absorbed as heme iron (iron bound to hemoglobin or myoglobin) or
as free Fe²⁺. In the intestinal cells, "heme iron" is degraded and free
Fe²⁺ is released. The free Fe²⁺ binds to apoferritin and is transported into
the blood.

- Free Fe²⁺ circulates in the blood bound to transferrin, which trans-
ports it from the small intestine to its storage sites in the liver, and from
the liver to the bone marrow for the synthesis of hemoglobin.

- Iron deficiency is the most common cause of anemia.