GI Long Notes PDF

GI-HUF1 PS LEUNG 2018-2019
GASTROINTESTINAL PHYSIOLOGY 2018 - 2019
MEDU2400 Human Function 1 - GI Physiology
OVERALL OBJECTIVE:
• To acquire the basic concept and principle of GI physiology
• To apply this basic science knowledge to GI pathophysiology
LECTURE:
1. Overview of GI System
2. Regulation of GI Function
3. GI Motility
4. Gastric Physiology
5. Salivary and Pancreatic Physiology
6. Hepatobiliary Physiology
7. Digestion and Absorption I
8. Digestion and Absorption II
9. Digestion and Absorption III
10. GI Disorder I
11. GI Disorder II
TUTORIAL:
1. GI Motility: Esophageal Dysfunction
2. GI Secretion: Gastric Secretion Dysfunction
3. Digestion & Absorption: Amino Acid Transport Dysfunction
RECOMMENDED READING:
• Gastrointestinal System: Gastrointestinal, Hepatobiliary and Nutritional Physiology, 1st ed.,
PS Leung, Springer, Dordrecht, 2014
• Gastrointestinal Physiology, 8th ed., LR Johnson, Mosby, St. Louis, 2014
RESPONSIBLE TEACHER:
Professor LEUNG Po Sing ( )
Room 609A, Lo Kwee-Seong Integrated Biomedical Sciences Building
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong
Tel: 3943 6879; Fax: 2603 5123; E-mail: psleung@cuhk.edu.hk
*I declare that all materials presented here are for the purpose of teaching only.
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LECTURE 1: Overview of GI System
Learning objectives
• Appreciate the physiological roles of different parts of GI tract and its associated organs
• Describe the structural organization and specialization of various regions of GI tract
• Understand the GI function in term of motility, secretion, digestion and absorption
• Integrate and collate the structure- and- function relationship of the GI system
1. Introduction
The Gastro-Intestinal (GI) system is divided into two parts: the luminal GI and hepato-biliary-
pancreatic GI. The luminal (or tubular) GI consists of the alimentary (digestive) canal or GI tract,
which extends from the mouth to the anus. The GI tract includes the pharynx, esophagus, stomach,
small intestine (duodenum, jejunum and ileum) and large intestine (colon, cecum and rectum), as
well as the anus (Fig. 1-1). The GI tract is a muscular tube of about 5m long when one is alive; its
length can be doubled to 10m, due to the loss of muscle tone during autopsy or postmortem
examination. The GI tract can contract and relax with different transit time in each segment of the
tract with its respective passage time which, in turn, depends on its own specific function (i.e.
motility or secretion) of each segment (Fig. 1-2). The motor and secretory activities of the GI
system are highly controlled and integrated by the gut endocrine and enteric nervous systems (see
Lecture 2 & 3).
The hepato-biliary-pancreatic GI consists of the accessory or associated glands and organs. This
part includes the salivary glands, pancreas, gallbladder and liver, which empty their secretions
into the lumen of the GI (e.g. luminal digestive enzymes). The salivary glands secrete saliva for
digestion and lubrication (Lecture 5); the pancreas produces hydrolytic enzymes for the digestion of
our daily foodstuff and bicarbonate for the neutralization of our gastric contents (Lecture 4, 5, 7 &
8); the liver secretes bile which is stored temporarily in the gallbladder, and subsequently delivered
to the duodenum for the fat digestion and absorption (Lecture 6). There are key locations that
separate the GI tract from each other by “sphincters” (esophageal, pyloric, sphincter of Oddi,
ileocecal, and anal sphincters). Sphincter is made up of smooth muscle and it acts as a reservoir for
holding luminal content adequately before emptying into next segment by its highly coordinated
activity. Dysregulation of the sphincter activity results in GI motility disorder (see Delayed/Rapid
Gastric Emptying in Lecture 3; Achalasia/GERD in Lecture 3 & 10). As a basic concept,
dysfunction of either GI motility or secretion, or both, leads to some common GI disorders
including, but not limiting to, Gastro-Esophageal Reflux Disease (GERD), Peptic Ulcer Disease
(PUD), and Diarrhea (see Lecture 10 & 11).
In general, the overall function of the GI system is to take in nutrients and to eliminate waste. One
can survive with the loss of the GI system (except the liver) if one is fed parenterally and some vital
secretions (such as digestive enzymes, intrinsic factor and insulin) are replaced. Of note, the GI
tract is also an important part of the body’s immune system. The so-called Gut-Associated
Lymphoid Tissue or GALT (see Fig. 1-3 & Fig. 1-4) consists of both organized aggregates of
lymphoid tissue (e.g. Peyer’s patches) and diffuse (or migrating) populations of immune cells (e.g.
intraepithelial lymphocytes). The GALT has two primary functions: (1) protection against the
potential microbial pathogens and (2) permission of immunologic tolerance to both the potentially
immunologic dietary substances and bacteria that normally reside primarily in the lumen of the GI
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tract (called Intestinal Microflora/Gut Microbiota). The roles of GALT and intestinal flora, and
their clinical relevance to gut disease are adequately discussed below (see Section 3, p.4 &5).
Finally, the GI tract possesses two characteristic regulatory systems for GI functions: the Gut
Endocrine System and its own neural circuitry, the so-called Enteric Nervous System (ENS) (Fig.
1-3); the ENS functions independently from, but is under the influence of, the Autonomous &
Central Nervous Systems (ANS & CNS), as fully discussed in Lecture 2.
PASSAGE TIME
10 seconds
1 to 3 hours
7 to 9 hours
25 to 30 hours
30 to 120 hours
Fig. 1-1. The digestive tract and its associated glands Fig. 1-2. The time taken for food to pass through
and organs of GI system. various segments of the digestive tract in human.
2. Structural features of the GI tract
The structure of the GI tract varies greatly from region to region, but common features exist in the
overall organization of the tract wall (Fig. 1-3). From inside outward, there are 4 characteristic
layers. The first layer mucosa is the innermost layer and it consists of an epithelium, the lamina
propria, and the muscularis mucosae. Included in the epithelium are the exocrine gland cells and
endocrine cells, which secrete mucus and digestive enzyme into the lumen, and release GI
hormones into the blood, respectively. The endocrine cells are interspersed among epithelial lining
and they constitute the gut endocrine system (see Lecture 2). In the lamina propria, it contains
small blood vessels, nerve fibers, and lymphatic cells/tissues, called GALT (see also Fig. 1-4). In
addition, a thin muscle layer called muscularis mucosae is also found and its muscle activity is
responsible for controlling mucosal blood flow and GI secretion. The second layer submucosa is
a connective tissue with major blood and lymphatic vessels along with a network of nerve cells
called submucosal nerve plexus passing through. The third layer muscularis externa is a thick
muscle whose contraction contributes to major gut motility (segmentation and peristalsis). This
muscle layer typically consists of two substantial layers of smooth muscle cells: an inner circular
layer and an outer longitudinal layer. In addition, a prominent network of nerve cells called
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myenteric nerve plexus is located between the circular and longitudinal smooth muscle layers.
Together with the submucosal plexus, they constitute the ENS. Innervation of the GI tract and its
regulation will be discussed in Lecture 2. The fourth layer serosa is the outermost layer, which
consists mainly of connective tissue and it connects to the abdominal wall supporting the GI tract in
the abdominal cavity.
Note: The gut endocrine system and ENS are two major systems that are critical for the
regulation and integration of two primary GI functions, i.e. secretion and motility.
*Gut Endocrine System
*
Small BV
N. Fibers
Lymphatic
cells and tissues (GALT)
*ENS
Fig. 1-3. Structure of the GI wall in longitudinal section (Vander’s Human Physiology, 2011).
3. Gut-Associated Lymphoid Tissue (GALT)
• GALT, a part of mucosa-associated lymphoid tissue (MALT), plays an important role for GI
immune system; others in respiratory & urinary epithelium (see below, p.5)
• It consists of organized aggregates of lymphoid tissue (Peyer patches) and diffuse lymphocytes
(Intraepithelial lymphocytes)
• It is functionally and operationally distinct from the systemic immune system
• Over-activity in response to food, bacterial antigens and others triggers immunological reactions
thus mucosal inflammation
• Celiac disease and inflammatory bowel disease (IBD) e.g. Crohn’s disease and ulcerative colitis
see Clinical Correlations, CC, of this Lecture (p.9), and Lectures 6 (p.54), 8&9 (p.73) & 11 (p.87)
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Peyer patches or lymphoid nodules
Diffuse or migrating immune cells
Fig. 1-4. A schematic diagram showing Peyer patches and intraepithelial lymphocytes of the GALT in the lamina propria of
intestinal mucosa (Berne & Levy’s Physiology, 2008).
In general, the cells lining the luminal intestinal organs are exposed to hostile environments,
including antigens from food and bacteria, digestive enzymes and various solutions at variable pH
levels. In view of this fact, certain non-immunologic defense mechanisms are present to protect
against these potential hazards; they include gastric acid secretion, intestinal mucin, epithelial cell
permeability barrier and gut peristalsis that are critical for maintaining the ecology of intestinal
flora. In an individual with impaired small intestinal peristalsis, for example, abnormally higher
levels of bacteria will lead to diarrhea and/or steatorrhea (fecal fat excretion), a clinical condition
referred to as Intestinal Blind Loop Syndrome (see CC of this lecture).
Immunologically, GALT, a part of the body’s Mucosa-Associated Lymphoid Tissues (MALT)

which contributes significantly to our gut defense mechanism or GI immune system; MALT can
also be found in respiratory and urinary systems. Even though GALT has some interactions with
the systemic immune system, GALT is functionally and operationally distinct from the systemic
system. There is evidence of communication between the GALT and other MALT such as the
pulmonary epithelia, as manifested in asthma. The GALT system secretes antibodies in response to
specific food or bacterial antigens, and triggers immunological reactions against them, thus finally
leading to mucosal inflammation and damage. Activation of this local GI immune system is
involved in some of the common GI disorders including celiac disease (see CC of Lecture 8&9
& 11), and in inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn’s disease
(see CC of this Lecture and Lecture 6).
4. Functions of GI system
The physiological functions of the GI system can be described in terms of four processes: (1)
Digestion, (2) Secretion, (3) Absorption and (4) Motility, AND the Mechanisms controlling
them (Fig. 1-5). While digestion, secretion, and absorption are taking place, contractions of smooth
muscles in the GI tract wall mix the luminal contents with various secretions and move them
through the tract from proximal to distal regions, i.e. from the mouth to anus. These contractions
are referred to as the motility of the GI tract. Physiologically, the motility and secretion are finely
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tuned in order to achieve optimal digestion and absorption and thus assimilation of nutrients takes
place, which are the primary role of our GI system.
2 3
Fig. 1-5. Four processes carried out by the gastrointestinal tract of which absorption is central to these four activities (Vander’s
Human Physiology, 2011).
5. GI secretions
The major secretions from the exocrine glands and associated organs of the GI system consist of
inorganic ions, gastric juice, pancreatic enzymes and liver products, as well as small and large
intestinal mucin. The exocrine glands present throughout the GI system contain a variety of
secretory cells, each of which produces a characteristic secretion (see Table 1-1).
Table 1-1. Exocrine secretions of the GI system. Underlined sites are of associated organs/glands.
Site of secretion Exocrine secretory cells Secretory components
Entire All cells Water
GI system Inorganic salts
Salivary Serous Amylase
Glands Mucous Mucin
Esophagus Mucous Mucin
Stomach Parietal HCl & Intrinsic factor
Chief Pepsin
Mucous Mucin
Pancreas Acinar Amylase
Protease
Lipase
Others
Duct cells Bicarbonate
Liver Hepatocytes Bile salts

Duct cells Bicarbonate
Small and Large Mucous Mucin
Intestine
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All these secretions contain water and inorganic ions, but much also contain organic constituents.
Important inorganic ions are hydrogen ions secreted by the stomach and bicarbonate ions
secreted by the pancreas. The most notable of the organic components are the digestive enzymes of
the salivary glands, stomach, and pancreas; the bile salts, bile pigments, and cholesterol secreted by
the liver; and mucin produced by all regions of the digestive tract. The exocrine secretory cells of
the GI system, their sites of secretion, and the major components of these secretions are
summarized in Table 1-1.
Apart from major exocrine secretions, the GI system can secrete an array of endocrine, paracrine,
and neurocrine substances, mainly peptides in nature, which are very important in the regulation
of GI functions (see Lecture 2). These regulators will be found as key players throughout the
lectures of this course. An Appendix Table summarizing various secretory products in the forms
of exocrine, endocrine, paracrine and neurocrine, and their clinical manifestations of our GI system
is shown at the end of this GI notes (see p. 88).
SUMMARY
The GI system is massive in size compared to all other organ systems; it consists of esophagus,
stomach, small intestine, large intestine, gallbladder, liver, and pancreas. Thus complex
control mechanisms are needed to integrate these seven organs together. Among the organs in the
GI system, the liver has numerous functions. In our GI course, ONLY GI function related to
exocrine bile secretion by the liver, i.e. hepatobiliary physiology will be focused (see Lecture 6).
The major functions of the GI system are: secretion, motility, digestion, absorption, metabolism,
and defense mechanisms as well as immunity. In brief, the GI system is a complex system of
organs concerned with two primary roles, namely digestion and absorption, thus rendering to
assimilation of nutrients by the human body. To fulfill these functions, the GI system exhibits four
distinct types of physiological activities:
• Motor activity: chewing, swallowing, mixing, propulsion and storage

• Secretory activity: water, electrolytes, mucus and digestive juice
• Digestive activity: breaking-down of food particles into absorbable forms
• Absorptive activity: transport of nutrients, fluid and electrolyte
All these four activities are finely regulated by highly sophisticated mechanisms via Enteric
Nervous System (ENS)/Autonomous Nervous System (ANS) and the Gut Endocrine System.
In addition, GALT contributes significantly to gut immune function. Regulation of GI functions

will be discussed in Lecture 2.
GI Physiology vs Gastroenterology
In term of clinical setting, the students are encouraged to integrate and collate all the basic science
knowledge into one system. In the GI system, for example, the students are immersed for a
concentrated period of time when all basic science disciplines of the GI are covered; they include
physiology and pathophysiology along with histology, embryology, pharmacology and
microbiology of the gut. In view of this, some very basic knowledge of the GI embryology and
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histology as well as pharmacology and microbiology should be grasped by this GI course (See
“Tips on” in CC of this GI notes”).
Among them, GI physiology is the study involving physiological concepts and processes of the GI
system while gastroenterology is the study of diseases affecting the GI system including the
stomach, intestine, gallbladder, bile duct, liver and pancreas.
Figure 1-6 summarizes how to integrate the basic GI physiology, via its interaction with those GI
histology, embryology, microbiology and pharmacology, to GI pathophysiology.
Fig. 1-6. A schematic diagram showing how to apply the basic GI physiology to GI pathophysiology.
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CLINICAL CORRELATIONS
1. Tips on GI Embryology and GI Histology
For the sake of this GI course, some very basic knowledge of the GI embryology and histology
should be grasped by the first/second year medical students in order to integrate the GI physiology
into pathophysiology.
The primitive gut tube is developed from the dorsal part of the embryo yolk sac and divided into
the foregut (esophagus, stomach, liver, gallbladder, pancreas and upper duodenum), midgut (lower
duodenum, ileum, cecum, appendix, ascending colon and proximal to third of the transverse colon),
and hindgut (distal one third of the transverse colon, rectum, and upper anal canal). The primitive
gut tube is composed of two layers: an inner layer of endoderm that lines the lumen and an outer
layer of visceral mesoderm. Histologically, the general plan of the GI tract consists of mucosa
(epithelial lining and glands, lamina propria, and muscularis mucosae), submucosa, muscularis
externa, and serosa, as described above (Fig. 1-3). Embryologically, the epithelial lining and
glands of the mucosa are derived from endoderm, whereas the other components are derived from
visceral mesoderm. Early in development, the epithelial lining of the gut tube proliferates rapidly
and obliterates the lumen. Later in development, recanalization occurs. Clinically, rectal atresia
occurs when the anus is both present and open, but a variable segment of rectum above it is atretic.
The anal canal and rectum are present but remain unconnected because of either abnormal
recannalization or a compromised blood supply (i.e ischemia) causing focal atresia. On the other
hand, ectopic anus (imperforate anus) occurs when the hindgut ends as a blind sac because of the
abnormal formation of the urorectal septum. See also CC of Lecture 3, Hirschsprung’s disease,
p.29.
2. Clinical Focus
INTESTINAL BLIND LOOP SYNDROME
• Bacterial overgrowth occurs in such a condition as the stasis of proximal intestinal contents (also
called stagnant bowel syndrome) due to motility dysfunction in small intestine.
• Impaired gut peristalsis that may be created after surgery leads to overgrowth of bacteria,
particularly anaerobic ones in proximal intestine.
• Anaerobic bacteria facilitate deconjugation (usually occurs in distal intestine) of bile acids which
are readily and passively absorbed than conjugated ones in proximal intestine (why? see Lecture
6).
• Decrease in concentration of the intraluminal bile acids leads to fat maldigestion and
malabsorption, thus diarrhea and steatorrhea (Cf. diabetic diarrhea of Lecture 3, p.29).
• Compare with different GI motility disorders covered in this course. See Achalasia/GERD in
esophagus; Gastroparesis/Dumping Syndrome in stomach; Congenital Megacolon in large intestine;
see also CC, p.29 of Lecture 3, Tutorial 1, and Lecture 10).
INFLAMMATORY BOWEL DISEASE (IBD)
• The pathogenesis of IBD is unknown which is probably due to the involvement of genetic,
immunological, microbial, and environmental factors; however, activation of the GALT should
have a role in IBD.
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• Two common clinical manifestations are Ulcerative Colitis (UC) and Crohn’s Disease (CD).
• UC is an inflammation limited to the colon or rectum, typically with bloody diarrhea.
• NSAIDs are the first-line treatment, followed by glucocorticoid therapy; colectomy removes the
disease and is a definite cure.
• CD is an inflammation affecting any part of GI tract, most often in terminal ileum; it is
characterized by abdominal pain and weight loss but less bloody diarrhea.
• Apart from anti-inflammatory drugs, surgical option is the final treatment, such as ileal resection.
• Ileal resection results in a decreased reabsorption of bile acid from distal ileum (see CC, Lecture
6, p.54) via enterohepatic circulation (see Lecture 6, p.50), and thus leads to secretory diarrhea
(see CC, Lecture 6, p54 & Case Study, p,56).
APPENDICITIS
• The appendix is a small fingerlike projection from the cecum, being a blind-end pouch without
essential function in digestion except mucus secretion and, like the tonsils, containing lymphoid
tissues (GALT) to produce antibodies and thus it is subject to inflammation.
• Appendicitis is characterized by acute abdominal pain in the lower right quadrant of the abdomen
with elevated level of a-amylase; Cf other conditions with raised a-amylase levels, e.g. acute
pancreatitis (see Case Study of Lecture 5, p.46); if ruptured, infectious material can spread
throughout the surrounding body cavity, leading to fatal peritonitis.
• Apart from using antibiotics, appendectomy or surgical removal of the inflamed appendix is the
common treatment of this condition.
• Differential diagnosis: complications of pregnancy, urinary tract infection, and other GI problems
should be excluded.
3. Case Study
A 23-year-old PhD student presents with the Specialist Clinic in PWH with abdominal pain,
bloating and altered bowel habit. She is relieved with a bowel movement and diarrhea. She has
otherwise no significant medical history. The patient denies rectal bleeding, weight loss, or
nocturnal symptoms. The physical examination is normal, and limited testing reveals no evidence
of thyroid disease or laboratory abnormalities. The patient responds to dietary counseling,
reassurance, and increased fiber diet.
Resolution: Irritable Bowel Syndrome (IBS)
• Compare and contrast IBS with IBD

• IBS is the commonest condition seen by gastroenterologists. It is characterized by abnormally
increased GI motility, generally associated with emotional stress. Most of those affected are
young adults, twice as prevalent in women, who complain of nonspecific diarrhea (with or without
alternating constipation), bloated feeling and, occasionally, lower abdomen pain and cramps. The
pain is usually relived by moving the bowels
• In diagnosis, other conditions such as dysentery, lactose intolerance and IBD must be ruled out
• Because there is no organic disease present in IBS, specific treatment is not necessary.
Reassurance, dietary advice (high-fiber containing food) and anti-diarrheal drugs (such as anti-
spasmotics that act on GI smooth muscle), and some other drugs, if deemed (such as mild
tranquilizers and anti-depressants) may be used for the patients
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LECTURE 2: Regulation of Gastrointestinal Function
Learning objectives
• Appreciate how the GI functions are highly regulated in terms of motility and secretion
• Understand the regulatory pathways of GI hormones, paracrines and neurocrines
• Explain why the GI system requires such a complex control mechanism
• Describe how the ENS differs from the ANS and endocrine system
• Apply the dys-regulation of GI functions to GI disorders
1. Functions of GI system
The function of the GI system can be best described in terms of four processes:
• Motility
• Secretion
• Digestion
• Absorption
Generally speaking, digestion and absorption are, per se, not regulated. However, motor and
secretory processes are finely subjected to neural and hormonal regulation, and thus optimize
digestion and absorption of nutrients that take place in the GI tract.
2. Basic mechanisms that control the GI motility and secretion
Unlike the control systems that regulate variables in the internal environment, the control
mechanisms of the GI system regulate conditions in the lumen of the tract. With few exceptions,
these control mechanisms via GI reflexes are governed NOT by the nutritional state of the body,
BUT by the volume and composition of the luminal contents. GI reflexes are initiated by
relatively small number of stimuli from luminal contents; they include:
• Distension (luminal contents)

• Acidity (pH of chyme)
• Osmolarity (solute concentration of chyme)
• Digestion products (fatty acids, peptides and amino acids)
The above stimuli act on the receptors of sensory neurons from ENS and/or chemoreceptors
from endocrine cells located in the GI tract wall so as to trigger motor and secretory responses via
neurohormonal regulatory pathways.
• Mechanoreceptors
• Osmoreceptors
• Chemoreceptors
While the sensory neurons of the ENS can act as all of the above-mentioned receptors (i.e.
mechanoreceptors, osmoreceptors & chemoreceptors), the endocrine cells of the gut endocrine
system that produce GI hormones act as chemoreceptors for food stimuli.
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3. Neurohormonal regulation
Because the size of the digestive system (seven organs), the complexity of function of each organ,
and the interaction among different parts of the GI tract, an intricate neural and hormonal system is
required for the integration and regulation of GI function. In many instances the mediators of
neurohormonal control in the GI system are of peptides in nature.
This lecture will focus on the regulatory mechanisms for the GI function whereby the extrinsic
and intrinsic nervous regulatory pathways as well as hormonal, paracrine and neurocrine
pathways are highly integrated into ONE control system.
4. Innervation of the GI tract
GI functions are regulated by three different nervous systems: the Central Nervous System
(CNS), Autonomous Nervous System (ANS), and Enteric Nervous System (ENS).
• Extrinsic (autonomous) nervous system: parasympathetic and sympathetic divisions

• Intrinsic (enteric) nervous system: myenteric plexus and submucosal plexus
- Myenteric plexus controls mainly the GI movements (smooth muscle activity)

- Submucosal plexus controls mainly GI secretion (secretory activity) & local blood flow
- ENS can function on its owns (sensory, interneuron & motor), independent of the ANS
- ANS can, however, modulate the GI functions through its interaction with the ENS
As the ENS contains as many neurons as the spinal cord, it is sometime called the “little” or
“second” brain.
4.1. Extrinsic nervous system

Extrinsic innervation of the GI tract is provided by the ANS, i.e. parasympathetic and sympathetic
divisions (Fig. 2-1). Parasympathetic innervation is supplied primarily with the vagus and pelvic
nerves. Long preganglionic axons arise from cell bodies within the medulla of the brain (vagus
nerves) and the sacral region of the spinal cord (pelvic nerves). These cholinergic or acetylcholine
(ACh)-releasing nerves enter various parts of the GI tract where they synapse mainly with cells
of the ENS (Fig. 2-1A). For example, the vagus nerves innervate on the smooth muscle of the
lower part of esophagus down to the transverse colon; the pelvic nerves innervate from the
descending colon down to the rectum. In addition, these same nerve bundles contain many afferent
nerves whose receptors lie within the various tissue of the gut; these nerves project back to the
brain and spinal cord to provide sensory inputs for integration.
On the other hand, sympathetic innervation is supplied by nerves that run between the spinal cord
and the prevertebral ganglia and between these ganglia and the organs of the gut. Postganglionic
adrenergic or noradrenaline (NA)-releasing fibers from these ganglia innervate primarily onto
elements of the ENS (Fig. 2-1B).
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In general, stimulation of the parasympathetic enhances the activity of most GI functions but NOT
in all cases. It is because some of the enteric neurons are inhibitory in nature, thereby inhibiting
certain of the functions. On the other hand, stimulation of the sympathetic system inhibits activity
of GI functions, thus causing many effects opposite to those of the parasympathetic system. Put it
simply, sympathetic innervation exerts its effects in two ways: (1) by direct inhibitory action
of the NA on the smooth muscle to a lesser extent; (2) by inhibitory action of the NA on the
ENS neurons to a greater extent.
Fig. 2-1. Schematic diagram showing the extrinsic nervous system: (A) Parasympathetic nervous system. Dashed line indicate
cholinergic innvervation of the striated muscle in the esophagus and external anal sphincter. (B) Sympathetic nervous system.
Dotted lines indicate the afferent and postganglionic efferent innervation. C, celiac; SM, superior mesenteric; IM, inferior
mesenteric (Johnson’s Essential Medical Physiology, 2003).
4.2. Intrinsic nervous system

The GI system has its own local nervous system, called the ENS, predominantly in the form of two
nerve networks, the myenteric plexus and the submucosal plexus. The ENS contains adrenergic and
cholinergic neurons as well as the so-called Non-Adrenergic and Non-Cholinergic (NANC)
neurons. NANC release a diverse neuro-regulators including peptides (e.g. VIP) and non-peptide
(e.g. nitric oxide and ATP). These neurons synapse onto the smooth muscles, glands and epithelial
cells. The effectors are supplied by neurons that are part of ENS. This permits neural reflexes that
run completely within the tract, i.e. short reflexes which are independent of the CNS.
In addition, long reflexes from receptors in the tract send signals to the CNS by way of afferent
nerves and back to the nerve plexuses and effectors by way of parasympathetic and sympathetic
nerve fibers. Via these pathways, the CNS can influence the motility and secretory functions of the
GI tract (see Fig. 2-2).
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& hunger
Relay to CNS Via ANS Back to ENS
*
ENS
Fig. 2-2. Long and short neural reflex pathways initiated by stimuli in the gastrointestinal tract. The short reflex is initiated from
receptors through the nerve plexuses of ENS to effector cells. The long reflex utilizes neurons that link the central nervous
system to the gastrointestinal tract (Vander’s Human Physiology, 2011).
5. Pathways for neurohumoral regulation
In addition to the classical neurotransmitters, like acetylcholine and noradrenaline, the most
abundant class of transmitters in the ENS and neuroendocrine cells of the GI system are regulatory
peptides.
The enteroendocrine cells are members of a widely distributed system termed Amine Precursor
Uptake and Decarboxylation (APUD) cells. APUD cells are all derived from neuroendocrine-
programmed cells originating in the embryonic ectoblast. Each peptide may have a variety of
functions, depending on the site tested.
Regulatory peptides may be released as neurotransmitters, paracrine/autocrine transmitters, or

endocrine hormones. Peptides and derivatives of amino acids are released from ENS and endocrine
cells of GI mucosa.
• All GI hormones are peptides

• Not all peptides found in GI tract are hormone
• Based on the method by which the peptide is delivered to its target site, GI peptides can
be classified into 3 types (Fig. 2-3):
- Endocirne: peptides
- Paracrine: peptides or nonpeptides
- Neurocrine: peptides or nonpeptides
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Fig. 2-3. Regulatory pathways for gastrointestinal functions. E=Endocrine; P=Paracrine; N=Neurocrine. It is noted that each
regulatory pathway does not occur as an isolated event but that all may integrate into one control mechanism (Johnson’s GI
Physiology, 2007).
5.1. Endocrine pathway
Four criteria must be met for “true hormones”:

1. A physiological stimulus, such as the presence of food, applied to one part of the GI tract
produces a response in another part
2. The response could be elicited after denervation between the two parts of the tract
3. An extract of mucosa taken from the site where the stimulus was applied reproduces the response
when injected into the blood
4. The substance must be isolated, purified, identified chemically, and synthesized
Hormones are released from GI endocrine cells into the portal circulation, pass through the liver,
and are then circulated to all tissues of the body (unless excluded from the brain by the blood-
brain barrier). Target tissues are those that have specific receptors for the hormones in their
plasma membranes. Thus specificity is a property of the target tissue.
Five GI peptides have satisfied these criteria and are classically considered as true hormones (see
Table 2-1). They are, in the order of their discovery, Secretin, Gastrin, Cholecystokinin (CCK),
Gastric Inhibitory Peptide/Glucose-dependent Insulinotropic Peptide (GIP), and motilin. GIP
and glucagon like peptide-1 (GLP-1) are released from GI endocrine cells, namely K-cells and L-
cells, respectively. Both peptides belong to incretin (intestinal) hormones, which have positive
effects on pancreatic beta-cell structure and function.
Note: GLP-1 is also classified as one of the GI hormones.
There is also an extensive list of peptides found in endocrine cells of the GI tract, whose members
for one reason or another have failed to satisfy one of the above criteria. These substances are
called “candidate hormones”. They include, but name a few, Pancreatic Polypeptide (PP),
Peptide YY (PYY), and enteroglucagon. See also Appendix Table, p.88.
Table 2-1. Five true hormones established in the GI system.
15
Hormones Actions Release sites Stimuli

Secretin Stimulation of pancreatic Duodenum (S-cells) Acid
(27 a.a) & biliary HCO3-
secretion, and growth of
exocrine pancreas;
inhibition of gastric
emptying
Gastrin* Stimulation of acid and Gastric antrum (G-cells) Amino acids, peptides,
(17/34 a.a.) growth of gastric oxyntic distension & vagal
gland mucosa Duodenum (G-cells) stimulation
CCK Stimulation of Duodenum (I-cells) Fatty acids, peptides &
(8/33 a.a.) gallbladder contraction, amino acids
pancreatic enzyme Jejunum (I-cells)
secretion; inhibition of
gastric emptying
GIP Stimulation of insulin Duodenum (K-cells) Amino acids, fatty
(42 a.a.) release; inhibition of acid acids & glucose
secretion Jejunum (K-cells)
Motilin Stimulation of gastric & Duodenum Fats, acids & nerves
(22 a.a.) intestinal motility
Jejunum
Note: In a clinical condition, a patient has elevated levels of serum gastrin, which is released from a
pancreatic islet cell adenoma (not from gastric antral G-cells), called “Gastrinoma”. This
clinical picture is known as Zollinger-Ellison syndrome. A gastrinoma is a tumor of the endocrine
pancreas consisting of G-cells which secrete gastrin even though G-cells are not normally found
within the endocrine pancreas. Because gastrin release in such a condition is NOT under
physiological control, but rather is continuously released, acid secretion is substantially increased,
thus leading to severe duodenal ulcer and persistent diarrhea. For further discussion, see
Tutorial 2 and Lecture 10 (p.77 & 78) & 11 (Table 11-2, p.82).
5.2. Paracrine pathway

Paracrine agents are synthesized in and released from endocrine cells in the same fashion as
hormones either in the form of peptides or non-peptides.
However, the amounts released do not reach the general circulation. Instead, paracrines act on cells
in their immediate vicinity, reaching them by simple diffusion.
• Somatostatin
- The only GI peptide that functions physiologically as a paracrine

- It exists throughout the GI mucosa (e.g. D-cells) and the pancreas (delta-cell)
- It inhibits the release of gut hormones and intestinal secretion (see CC)
- One important function is to mediate gastric acid secretion by inhibiting gastrin release
from antral G cells and directly HCl release from parietal cells
• Histamine
- The other significant paracrine agent in gut physiology is histamine
- Histamine is not a peptide and it is a derivative from the amino acid histidine
- It is synthesized by endocrine-like cells, called EnteroChromaffin-Like (ECL) cells throughout
the GI mucosa (e.g. in the stomach)
- Its main function in GI physiology is to stimulate gastric acid secretion
16
- Its interaction with gastrin and acetylcholine can greatly potentiate gastric acid secretion by the
parietal cells (see Lecture 4)
5.3. Neurocrine pathway

GI peptides and/or non-peptides are released in nerve terminals throughout the mucosa and smooth
muscle of the gut. These neuropeptides can act as neurotransmitter and/or neuromodulator in
regulating GI function.
• Vasoactive intestinal peptide (VIP)

- Its main functions are to relax sphincters/gut circular muscle, and stimulate pancreatic/intestinal
secretion, as well as regulating blood flow
Note: Dysregulation of VIP secretion may lead to such clinical conditions of motility and
secreotory dysfunctions as Achalasia (see Tutorial 1 & Lecture 10) and Pancreatic Cholera,
respectively (see also Case Study in CC of this Lecture).
• Gastrin releasing peptide (GRP) or Bombesin

- It is released by vagal stimulation and appears to mediate vagally stimulated gastrin release in
gastric mucosa
• Acetylcholine (Ach)
- It is released from the nerve ending of neurons. It acts as a stimulatory regulator in GI function,
notably in acid secretion
SUMMARY
The regulatory mechanisms for GI secretion and motility are highly integrated by neural, hormonal,
and paracrine control pathways. The neural control is achieved by both extrinsic nerves of the ANS
and intrinsic nerves of the ENS of the GI tract. In many instances the regulators of neurocrine,
endocrine and paracrine control systems are peptides and, in some cases, a given peptide acts as
both a neurotransmitter and a hormone. The students should appreciate the importance of the ENS
in the control of GI function. The ENS is a complex network of nerve fibers and ganglia. Nerve cell
bodies are located in either the external muscle layer (myenteric plexus) or submucosa (submucosal
plexus). The ENS contains about 108 neurons, as many as the spinal cord and is thus called the
“gut-brain”. Neurons in the two plexi connect sensory fibers with fibers that innervate smooth
muscle and secretory cells. This arrangement allows for the local control of gut activity.
Although the ANS has important effects on GI function, these are achieved via its connections with
the ENS, i.e. unlike other tissues; autonomic fibers to the GI tract do not generally and directly
innervate their target cells. The complexity of the ENS is remarkable and appears increasingly so
with the discovery of new transmitters and new ways that transmitters interact with each other and
with target cells. Transmitters in the ENS mirror the diversity of those found in the CNS, such that
the largest number of transmitters is known as brain-gut peptides. Perhaps the most important
neurotransmitter discovered in the past decade, however, is not a peptide but nitric oxide, which is
the leading candidate transmitter to mediate many NANC inhibitory reflexes. These include
esophageal and intestinal peristalsis, inhibition of mucosal secretion, and relaxation of all GI
sphincters. Many of these transmitters have been shown to have clinical and pathophysiological
significance (see Appendix Table, p.88).
17
Finally, GI peptides play a myriad role in GI physiology, which act as endocrine, paracrine and
neurocrine. Of note, the GI peptides can be divided into structurally homologous peptide families,
based on their amino acid identity located at the N-terminal and C-terminal, or throughout the
sequence. Because of the structural similarity, member of each peptide family shares structure-
activity (function) relationship (SAR) with each others. One of these peptide families is gastrin
and CCK with CCK-B and CCK-A receptors, respectively, as they have 4-amino acid identity in
their C-terminal. Because of the structural similarity, CCK has some gastrin activity and CCK
binds selectively to the CCK-A, whereas CCK and gastrin bind to the CCK-B receptor. Another
group of peptide family, called secretin family, is homologous to secretin and includes VIP, GIP,
GLP-1, and glucagon; their biological activity requires structural similarity throughout the
entire amino acid sequence.
The following are some of the key points of this lecture:
• The GI function is regulated by the extrinsic, intrinsic, and hormonal mechanisms via
endocrine, paracrine and neurocrine pathways.
• Each regulatory mechanism does not occur as an isolated event but all integrate into one
control mechanism.
• Extrinsic nerves alter hormone release, which are in turn affected by paracrine agents.
• One representative example is the control of gastric acid secretion, where extrinsic nerves, local
enteric reflexes, paracrines, and hormones act in a highly integrated manner.
18
1. Clinical Note
Several peptide hormones play important roles in food intake and thus regulate hunger, satiety,
obesity, and metabolic rate. These hormones are released from the pancreas (Insulin), adipose
tissue (Leptin), GI tract (CCK, PYY & GLP-1), and stomach (Ghrelin).
• GHRELIN
Signals from the stomach and small intestine regulate hunger and satiety, including such GI peptide
hormones as ghrelin, CCK & PYY. Ghrelin is a 28-a.a. peptide secreted by GI endocrine cells in
the oxyntic gland area of the stomach. As a regulator of food intake (appetite-enhancer), plasma
levels of ghrelin increase during fasting and fall during feeding. Interestingly, ghrelin levels are
raised in dieters who try to lose weight. If corrected, it may explain why it is so difficult for most
dieters to maintain their weight loss!
• LEPTIN
Leptin is a 167-a.a. polypeptide hormone released from fat cells, which acts as a circulating satiety
factor (appetite-suppressant). Rather than regulating meal-to-meal food consumption as ghrelin,
leptin helps maintain the body’s usual level of adiposity (fat storage).
• GLP-1
Glucagon-like peptide-1 (GLP-1) is secreted into the bloodstream (an endocrine) by the
enteroendocrine L cells in the lower intestine. GLP-1 is a 30-amino acid peptide of the secretin
family, with a 50% sequence similarity with glucagon. The glucagon gene is composed of six exons
that yield preproglucagon. In the pancreatic a-cells, preproglucagon is processed to glucagon and
glucagon-related polypeptide. In the intestinal L cells, preproglucagon is processed to GLP-1 and
GLP-2, and glycentin.
Functions and regulation of GLP-1:

(i). It increases insulin secretion in the presence of hyperglycemia
(ii). It decreases postprandial glucagon secretion
(iii). It inhibits gastric emptying
(iv). It reduces food intake
(v). It stimulates pancreatic b-cell proliferation
(vi). Its secretion is enhanced in the presence of glucose, amino acids/small peptides and fatty acids
upon their arrival in the small intestine.
GLP-1 vs GIP
Both peptides are incretin (intestine secretion insulin) hormones released from intestinal endocrine
cells in response to glucose and nutrient stimuli [see point (vi) above] and they exert their effects by
binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R).
Specifically, GIP is secreted into the bloodstream by the enteroendocrine K cells in the upper
intestine. It is a 42-amino acid peptide of the secretin family. Compare the functions and
regulation of GLP-1 and GIP.
19
Note: The action of GIP and/or GLP-1 to increase insulin secretion explains why an oral glucose
load is utilized by cells more rapidly than an intravenous glucose load (see also “early insulin
secretion” in CC of Lecture 3, p.29).
GLP-1 based therapy for diabetes

GLP-1 has a short half-life (1-2 min) due to the rapid degradation of its N-terminus by an enzyme,
called dipeptidyl peptidase IV (DPP-IV). As such, inhibition of this enzyme by a DPP-IV
inhibitor (e.g. Sitagliptin, an FDA approved oral hypoglycemic drug from Merck) is beneficial as
it can prolong the action of GLP-1 in the blood. Interestingly, a naturally occurring peptide in the
saliva of the Gila monster, called exendin-4 shares sequence similarity with GLP-1; however,
exendin-4 has a prolonged half-life because it is resistant to DPP-IV degradation. The drug
exenatide is a synthetic exendin-4 which is the first GLP-1 based drug for the treatment of diabetes
approved by the FDA. Of note, pharmacological levels of GLP-1, but not GIP, preserve
insulinotropic actions in type 2 diabetic patients, which lead to the development of GLP based, but
not GIP based anti-diabetic drugs.
2. Case Study
A 40-year-old man presents with symptoms of severe watery diarrhea and occasionally flushing.
Despite of fasting for 48 hours, diarrhea is persistent (why? Hint: Osmotic vs Secretory diarrhea;
see Section 4.2, Lecture 11). His family doctor prescribes with antibiotics and anti-diarrheal
medications, but without any improvement of his symptoms. Upon admission to the hospital, he is
found to have serum electrolyte abnormalities (low serum Cl- and K+), severe dehydration, and
orthostatic (postural) hypotension, which can be corrected by intravenous fluid replacement.
Stool examination reveals no blood, pathogens, leukocytes, or fat. A computed tomography (CT)
scan of the abdomen shows a pancreatic mass and numerous lesions in the liver, consistent with
tumor metastases. Laboratory tests show that plasma VIP is markedly elevated.
Resolution: Pancreatic Cholera
• This man has a rare endocrine tumor of the pancreas causing an overproduction of a GI peptide
called VIP, a clinical picture known as pancreatic cholera/watery diarrhea syndrome.
• VIP is a potent stimulus (secretagogue) for intestinal secretion of the fluid and electrolytes, and
thus its overproduction causes copious, “cholera-like” diarrhea.
• In this case, the receptors for VIP are located in the basolateral membrane and are coupled to
adenylyl cyclase. Upon activation, adenylyl cyclase generates intracellular cAMP which in turn
opens the apical Cl- channels, initiating secretion of Cl- ions, followed by loss of Na+ ions and water.
Compare with watery diarrhea in cholera (see Section 4.2.1, Lecture 11).
• VIP can also relax GI sphincters and circular smooth muscle, as well as regulating blood
flow; in this patient, VIP causes vasodilation thus facial flushing.
• VIP is typically found in neuroendocrine cells of the GI mucosa, which is an important NANC
peptide acting as neurocrine for gut function. In this case, however, VIP is abnormally produced
and secreted into the blood by an endocrine tumor arising from the pancreas, i.e. VIPoma.
• Hypokalemia occurs because of stool loss and hypovolemia-induced aldosterone effect.
• As the tumor is metastatic, surgical intervention is not feasible. For his diarrhea, Octreotide, an
analogue of somatostatin, can be used to effectively inhibit VIP release or synthesis by tumor
cells. In addition, somatostatin can counteract the secretory action of VIP, possibly by inhibiting
the activation of adenylate cyclase-mediated cAMP.
20
LECTURE 3: Gastrointestinal Motility
Learning objectives
• Appreciate the basic mechanisms whereby the motility of GI smooth muscle is regulated
• Describe the various patterns of GI contractions and its physiological significance
• Discuss the regulation of esophageal and gastric as well as intestinal motility
• Correlate this knowledge to the understanding of GI motility dysfunction
.
1. GI smooth muscle
Two types of muscles are found in the digestive system. Skeletal (striated) muscle is found in the
pharynx, the upper third of the esophagus and the external anal sphincter. All of the remaining
part of the GI tract is entirely composed of smooth muscle.
Smooth muscle in the GI tract is primarily located in 3 layers of muscles found in most luminal
organs (see Fig. 1-3, p.4): muscularis mucosae, circular muscle and longitudinal muscle
(muscularis externa). The muscularis mucosae are a layer of muscle that lies just inside the basal
lamina propria of the epithelial cells. This thin layer of smooth muscle is primarily involved in the
mixing function of fluid at the surface of the lumen. The circular and longitudinal muscle layers
constitute the majority of gut muscle and they contribute to major GI contraction, i.e.
segmentation and peristalsis.
1.1. Characteristics of smooth muscle

- Smooth muscle makes up all of the contractile tissue of GI tract, except in the pharynx, upper
one-third to one-half of the esophagus, and the external anal sphincter where striated/skeletal
muscle is found
- Smooth muscle is made of small, narrow and spindle-shaped cells

- The cells are arranged in bundles, which constitute the functional unit of gut muscle
- Within each bundle, the cells are connected both mechanically and electrically
- Because of the electrical coupling, it is the bundle, rather than an individual muscle cell that forms
the basic unit for propagation of action potentials
2. Three regulatory mechanisms that control the gut motility
Control of gut motility is dependent on hormones and reflexes involving the sympathetic,
parasympathetic and ENS, as well as involving the intrinsic properties of GI smooth muscle and
the coupling between smooth muscle cells.
2.1. Neural control

- The control system includes the ANS and ENS, which send cholinergic and adrenergic nerve
terminals to exert excitatory and inhibitory influences on the gut motility.
- They have also sensory receptors in the smooth muscle that make the initiation of the short and
long reflexes in the regulation of gut motor activity (see Fig. 2-2, p.14).
21
2.2. Hormonal control

- The control system includes such GI peptides in the form of endocrine/paracrine/neurocrine (e.g.
CCK, VIP), which are released from the gut in response to neural or food stimuli.
2.3. Myogenic control system

- Myogenic means contraction arising continuously in a muscle, which is independent of neural
or hormonal stimuli
- However, its activity is constantly being influenced by the neural and hormonal systems
- This spontaneous electrical activity of smooth muscle cells and the characteristics of its
conduction form the myogenic control system
- The continuous electrical activity is divided into 2 basic types (see Fig. 3-1):
• Slow waves: these are slow potential oscillations arising at a rate of 3 per minute in the stomach
and 12 per minute in the duodenum. Such spontaneous depolarization and repolarization cycles,
termed slow waves, are accountable for the Basic Electrical Rhythm (BER), and they determine
the maximal frequency of gut smooth muscle motility.
• Action potentials (Spikes): these occur at the crest of slow waves when a particular threshold
potential is reached. Such stimulated activities are accountable for the contractile event in the gut
smooth muscle and, unlike slow waves, they are short-lasting in nature. However, even in the
resting state, the muscle is under a certain tension, called basal muscle tone.
More excitable
~ -50 mV
4. G.I. Hormones/paracrines
Fig. 3-1 Relationship between slow waves, action potentials and generation of tension in GI smooth muscle. Note the slow waves,
spike potentials, total depolarization and hyperpolarization, all of which occur under different physiological conditions of the GI
tract. Contraction occurs when depolarization caused by slow wave exceeds a threshold, a burst of action potentials occurs. The
action potentials elicit a much stronger contraction than occurs in the absence of action potentials. The contractile force increases
with increasing number of action potentials (Guyton & Hall’s Medical Physiology, 2000).
In summary, when the potential becomes less negative, which is called depolarization of the
membrane, the muscle fibers become more excitable. When the potential becomes more negative,
which is called hyperpolarization, the fibers become less excitable.
The gut smooth muscle cells undergo spontaneous depolarization-repolarization cycles (slow
waves), known as BER. In the absence of neural or hormonal input (food stimuli), these
22
depolarizations are too small to cause significant muscle contractions; however, they maintain a
certain degree of tension, called muscle tone (see Fig. 3-1-1). Excitatory endocrines, paracrines
and neurocrines act upon the smooth muscle to further depolarize the membrane, thereby bringing
it closer to the threshold of contraction. Once the threshold is reached, action potentials (or spikes)
are generated, which superimpose on the peak of the slow-wave cycle. The number of spike fired
with each slow wave determines the strength of the muscle contraction. While the frequency of
contraction is dictated by the slow waves and remains essentially constant, the force of
contraction is determined by neural and hormonal input which, in turn, depends on the food
stimuli.
Fig. 3-1-1. Relationships of spike potential and slow waves, and their consequences on muscle contraction (upper
panel) and muscle tone (lower panel).
3. Types of GI movement
Gut motility is organized to optimize the processes of digestion and absorption. Thus contractions
of the gut perform three main functions:
• Mixing of ingested food with digestive secretions and enzymes

• Circulation of gut contents to facilitate contact with GI mucosa
• Net propulsion of the luminal contents to the anal direction
3.1. Segmentation
Segmentation contraction (non-propulsive annular) that is neither preceded nor followed by other
contractions has obvious mixing function (Fig. 3-1-2).
3.2. Peristalsis
Successive contraction (sequential annular) that is coordinated along a substantial length of the gut
serves conspicuous propulsion function (Fig. 3-1-3).
23
Fig. 3-1-2. Segmentation movements Fig. 3-1-3. Peristaltic contraction
3.2.1. Mechanism of peristaltic reflex

In the circular muscle of the small intestine, bolus distension, radial stretching or chemical stimuli
applied to the mucosa activate mechano- and/or chemo-receptors to cause a contraction above
(orally) the point of stimulus (via enteric ascending excitatory reflex), and a relaxation below
(anally) the stimulus (via enteric descending inhibitory reflex). The mechanistic pathways of
peristaltic reflex are illustrated in Figure 3-2.
In myenteric plexus
Ascending Descending
Excitatory Pathway Inhibitory Pathway
ENS
Neurons
(ACh, NA & NANC)
In submucosal plexus
CONTRACTION Above ¬ Point of Stimulation ® Below RELAXATION
Fig. 3-2. Diagram showing major neuronal pathways involved in the ascending excitatory and descending inhibitory reflexes
within the GI wall. In the center of the figure, there are two sensory neurons: a stretch-sensitive neuron in the muscle layer and
mechanosensitive/chemosensitive neuron in the mucosa. Stimulation of these sensory neurons results in activation of ascending
(oral) excitatory pathways and descending (anal) inhibitory pathways to circular muscle. Ach, Acetylcholine; Sub P, substance P;
VIP, vasoactive intestinal peptide; NO, nitric oxide (Berne & Levy’s Physiology, 2004).
24
3.3. Tonic contraction
- Complete tonic contraction is normally found in the GI tract sphincters

- Such a restrictive action of the sphincters aids the mixing of luminal content and allows it to pass
at proper times
- Elsewhere in the gut, the occurrence of complete tonic contraction is pathological, called spasm
GI smooth muscle contraction has two types: phasic and tonic. Phasic muscle contracts and relaxes
in a matter of seconds (i.e. phasically). This type of smooth muscle is present in the main body of
esophagus, gastric antrum and small intestine. Tonic muscle contracts in a slow and sustained
manner (i.e. tonically). The duration of tonic contraction can be minutes or hours. This type of
smooth muscle is present in the LES, pyloric sphincter, ileocecal sphincter, Sphincter of Oddi, and
internal anal sphincters. Whether the muscle is phasic or tonic depends on the properties that are
intrinsic to the muscle cells. Neurotransmitters and hormones alter the amplitude of phasic
contractions and the tone of tonic muscle.
3.4. Migrating motor complex (MMC)
- After 4-5 hr of a meal a peristaltic activity, known as MMC, occurs and repeats until the arrival
of next meal
- Such an interdigestive MMC is elicited by a 22-amino acid GI peptide, called motilin
- The function of this periodic MMC contraction is to propel residue of the previous meal and to
control bacterial growth in the gut, thus acting as housekeeper contractions.
4. Esophageal motility
4.1. Three principal motor functions of esophagus
- The obvious function of the esophagus is to serve as a conduit for and to propel swallowed
material to the stomach
- It prevents entry of air at its upper end by the upper esophageal sphincter (UES)
- It allows food bolus into the stomach and prevents the reflux of gastric contents at its lower end
by a structure, called lower esophageal sphincter (LES)
- Disorder in LES leads to reflux esophagitis (or GERD) and achalasia (see below)
4.2. Regulation of esophageal motility
Upon initiation of swallowing, UES opens & food is pushed into the upper esophagus by a
propagating contraction wave (peristalsis) that begins in the pharynx & ends up with LES.
The LES then relaxes to let food enter the stomach. This peristaltic wave is termed primary
peristalsis due to swallowing. Secondary peristalsis may also be initiated in the absence of
swallowing because of the distention of food bolus in the esophagus when the primary peristalsis is
insufficient to clear it into stomach. Both intrinsic and extrinsic nerves are necessary for peristalsis
to occur (Fig. 3-3).
25
Swallowing
Center
1
UES
2
Body
of
Esophagus
3
LES
LES
Fig. 3-3. Neural mechanism involved in the control of esophageal motility. Left, motor neurons reach the esophagus in branches
of the vagus nerves, and sensory feedback to the swallowing center is carried by vagal afferent fibers. Right, enlarged view of the
circled region of the esophagus to show vagal somatic motor neurons that innervate the striated muscle and upper esophagus, and
vagal visceral motor neurons that innervate the smooth muscle of the lower esophagus (Berne & Levy’s Physiology, 2004).
The LES has important function in allowing food to enter the stomach and preventing the reflux of
gastric contents back into the esophagus. Two disorders, namely Gastro-Esophageal Reflux
Disease (GERD) and Achalasia can be attributed to dysfunction of the LES (Further discussion of
achalasia, see Tutorial 1 and Lecture 10). The intrinsic and extrinsic innervation of the LES is both
excitatory and inhibitory. Vagal excitatory fibers are predominantly cholinergic. The relaxation of
the sphincter that occurs in response to primary peristalsis in the esophagus is mediated by vagal
fibers that control the circular muscle of the LES. Although the inhibitory neurotransmitter is not
known with certainty, it is thought that vasoactive polypeptide (VIP) and nitric oxide (NO)
mediate this relaxation of the LES (Fig. 3-4).
Fig. 3-4. The LES is innervated by both vagal excitatory fibers (VEF) and vagal inhibitory fibers (VIF). Relaxation of the LES is
associated with an increased frequency of action potentials in VIF and decreased frequency of action potentials in VEF (Berne &
Levy’s Physiology, 2004).
26
5. Gastric motility
5.1. Three major motor functions of the stomach
- Its muscle relaxes to accommodate large volumes during a meal, i.e. receptive relaxation
- Its contraction mixes ingested material with gastric juice, thus facilitating digestion, solubilizing
some constituents, and reducing the size of the particles, i.e. mixing and propulsion
- Its contraction propel material (gastric chyme) into the duodenum at a regulated rate so as to
provide optimal time for intestinal digestion and absorption, i.e. gastric emptying
5.2. Regulation of gastric emptying
- Gastric emptying is regulated at a rate optimal for digestion and absorption of a meal
- Too slow causes delayed emptying (Gastroparesis)
- Too fast causes rapid emptying (Dumping syndrome)
- Gastric emptying depends upon the physical and chemical composition of the gastric and
intestinal contents
- Receptor activation in the stomach and duodenum sensitive to distension, changes in osmolarity,
pH, or lipid content can trigger neural and hormonal pathways that regulate gastric emptying
- Intestinal phase pathways that inhibit gastric emptying are emphasized (Fig. 3-5).
Gastric chyme
L. Reflex
pH < 3.5 ANS
GIP CCK S. Reflex

CCCCCK
ENS
Fig. 3-5. Inhibition of gastric emptying. (a) Hormonal pathway. (b) Neural pathway (Rhoades & Pflanzer’s Physiology, 1996).
27
The excitatory influences that originate in the stomach are kept in check by inhibitory
mechanisms that originate in the duodenum so as to have gastric chyme delivered in metered
doses to the duodenum. These inhibitory mechanisms for gastric emptying, i.e. neural and
hormonal pathways, prevent the upper small intestine from being overwhelmed by material from
the stomach. In addition, various emotional states, such as anger, fear and depression, produce
changes in gastric motor activity.
Note: Disorders of gastric motility may lead to uncontrolled gastric emptying (see CC of this
lecture).
6. Intestinal motility
6.1. Motility of small intestine
- The segmentation, peristalsis and MMC are the three major movements in the gut
- One important characteristic of intestinal movement is slow-wave gradient
- All smooth muscle bundles in the intestine exhibit slow-wave electrical activity; the frequency of
the waves declines progressively from the proximal to distal region, i.e. the presence of slow-wave
gradient
- This gradient ensures that contractions normally propagate only onto the anal direction
6.2. Motility of large intestine
Colonic transit is very slow in comparison to the small intestine. This assists in the main function of
the colon, which allows optimal fluid and salt uptake, and the function associated with colonic
bacteria. Segmentation is the primary motility pattern (approximately three times per day) while
peristaltic movements move contents into the sigmoid colon and thus initiate the defecation reflex.
The anal canal is usually kept closed by internal and external sphincters. The latter can be
controlled voluntarily.
SUMMARY
• The GI motility is organized for optimal digestion and absorption functions.

• It is regulated by neural, hormonal and myogenic control systems.
• The rhythm of the GI tract is generated by myogenic system of the smooth layer that undergo
spontaneous depolarization and repolarization cycles, known as slow-waves which contribute to the
basic electrical rhythm (BER).
• The frequency of BER is determined by the slow-waves which is essentially constant.
• The force of contractions is determined by the number of spikes fired with each wave, which
depends in turn on the neural and hormonal input.
28
1. Clinical Note
Most disorders of gastric motility result in abnormalities of gastric emptying which is
physiologically regulated by hormonal (secretin, GIP and CCK) and neural (ANS & ENS)
pathways. Two major categories of gastric dysmotility are manifested clinically: (1) Delayed
gastric emptying and (2) Rapid gastric emptying. The generalized symptoms of both conditions
overlap to some extent, including early satiety, fullness, heartburn, nausea, anorexia and weight loss.
• DELAYED GASTRIC EMPTYING: GASTROPARESIS

Reduced gastric emptying is commonly observed in patients with diabetes mellitus (DM), which
may be related to impaired vagal activity because of autonomous neuropathy in patients with
DM. Vagotomy (cutting of vagus nerve), which is performed to reduce acid secretion in patients
with peptic ulcer disease, also delays gastric emptying. This condition is usually prevented by a
procedure called “Pyloroplasty”, in which the surgeon cuts and weakens the muscle in the pyloric
area. The common symptoms observed in delayed gastric emptying are belching and vomiting.
• RAPID GASTRIC EMPTYING: DUMPING SYNDROME

Fast gastric emptying often occurs in post-gastrectomy (partial or total removal of the stomach) in
patients with peptic ulcer disease and gastric cancer. A rapid rate of gastric emptying may result
in diarrhea due to the osmotic load placed in the small duodenum; it is associated with duodenal
ulcer, indicating that the acid entering the intestine cannot be neutralized before it damages the
duodenal mucosa; it also results in increased early insulin secretion because of excessively rapid
carbohydrate absorption (Why?), thus causing hypoglycemia and hypoglycemia-induced symptoms
(activation of sympathetic NS) e.g. sweating and palpitation. These problems can be improved by
small, regular and relatively iso-osmolar meals.
2. Clinical Focus
TYPE 1 DIABETES MELLITUS (T1DM)

• Absolute deficiency of insulin which is characterized by hyperglycemia and hyperlipidemia with
chronic complications (neuropathy, nephropathy and retinopathy)
• T1DM can affect gastric emptying, a condition called diabetic gastroparesis, as well as causing
diabetic diarrhea (Hints: autonomous and possibly enteric neuropathy in diabetes lead to impaired
fluid and electrolyte transport, and abnormal intestinal motility. See Case Study below.
HIRSCHSPRUNG’S DISEASE OR CONGENITAL MEGACOLON

• A functional obstruction of the colon characterized by the absence of ganglion cells in myenteric
and submucosal plexus; it is due to a congenital disorder with a failure to pass meconium (first
defecation) at birth thus severe chronic constipation in infancy (cf. Achalasia).
ACHALASIA
• A functional obstruction of the esophagus resulting from degeneration of myenteric plexus; Cf.
Congenital megacolon and Chagas disease; see Tutorial 1 and Lecture 10.
• Cf. Functional obstruction vs Structural obstruction (e.g. Esophageal stricture, see Lecture
10).
29
3. Case Study
A 23-year-old man with a history of T1DM since age 14 presents with severe constipation,
abdominal distention, and severe heartburn, especially in the supine position. Occasionally, he
experiences dysphagia (difficulty in swallowing), particularly when solid foods are ingested. In the
past several months, he has had abdominal discomfort and fullness immediately after eating small
amounts of food. On physical examination, he has diabetic retinopathy and moderately severe
peripheral neuropathy. Upper GI and small bowel barium X-ray studies reveal a dilated stomach,
retained food material, and retention of over half of the barium after 30 minutes. The small
intestine is noted to have some nonspecific dilatations. The colon is filled with feces.
Resolution: T1DM-induced GI dysmotility
• A major consequence of severe and long-standing DM is the development of peripheral and

autonomic neuropathy. The latter has numerous effects on bowel function, a major
manifestation being the development of abnormal gut motility.
• Because the extent and severity of autonomic dysfunction vary considerably from patient to
patient, the clinical presentation of patients are quite protean. Many patients experience esophageal
and swallowing symptoms as a consequence of altered or aberrant sphincter functions and/or
peristalsis. Secondary and tertiary contractions may become more pronounced and frequent (Cf.
Achalasia in Lecture 10). Loss of lower esophageal sphincter tone can result in symptoms of reflux
esophagitis (heartburn & chest pain) because of acid-pepsin injury of the esophageal lining.
• Autonomic neuropathy can also affect gastric emptying. The stomach becomes flaccid and antral
peristalsis is defective or lost. This condition, called diabetic gastroparesis, is not uncommon and
is shown above (see Clinical Note & Focus). Barium remains in the stomach ten hours after
ingestion, indicative of delayed gastric emptying.
• Autonomic neuropathy of the small intestine can cause intestinal stasis, a condition that favors
luminal colonization and overgrowth by bacteria. These organisms compete for luminal nutrients
can cause nutrient malabsorption and diarrhea. Cf. Intestinal blind loop syndrome (see Clinical
Focus, Lecture 1, p.9).
• The normal function of the colon and rectum is also frequently affected by diabetic autonomic
neuropathy. Patients can develop severe constipation or diarrhea. In addition, the loss of anal
sphincter tone and the afferent nerves required for sensing the presence of stool in the rectal vault
may develop. These patients may lose normal defecation function and experience fecal
incontinence. The treatment of intestinal complications associated with diabetes is particularly
problematic, as the neuropathy is usually irreversible. Cf. Congenital megacolon (see Clinical
Focus of this Lecture).
30
LECTURE 4: Gastric Physiology
Learning objectives
• List the different cell types that contribute to gastric secretions
• Appreciate the cellular mechanism of gastric acid secretion by the parietal cells
• Describe the neural and hormonal controls for gastric secretions
• Discuss the mechanism of gastric mucosal barrier and its implications on ulceration
1. Gastric secretions
Our stomach produces about 2L/day of gastric acid secretion/juice. Its high H+ ions (pH=1 to 2)
kill most of the ingested germs; it catalyzes the conversion of inactive pepsinogen to pepsin. The
presence of acid/pepsin begins the digestion of dietary protein. However, pancreatic proteases can
hydrolyze all ingested protein in the absence of pepsin. An important component of gastric juice is
Intrinsic Factor (IF), which binds vitamin B12 in the duodenum, allowing it to be eventually
absorbed in the distal ileum (see B12 absorption in Section 2.1, Lecture 8&9); it is the only
indispensable substance of gastric juice. Its deficiency, following gastric surgery or in pernicious
anemia, must take injections of B12 or oral B12 with IF. The surface epithelia cells of stomach
secrete mucus and bicarbonate that protect the mucosa from acid/pepsin erosion.
1.1. Components and function of gastric juice

• HCl
- Dissolve food particle
- Convert the inactive pepsinogen to the active pepsin
- Act as bacteriostatic to kill germs
• Mucus
- Serve as a protective coating and lubricant for the gastric mucosa
- Maintain pH of gastric mucosa near neutrality (i.e. Act as gastric mucosal barrier)
• Pepsin
- Digest protein
- Cleave pepsinogen to pepsin as a positive feedback process (see Section 2.3.2, Lecture 7)
• Intrinsic factor
- Bind vitamin B12 for its absorption in distal ileum
*For additional information on IF deficiency following pernicious anemia, please see CC.
2. Functional anatomy of the stomach

There are two functional portions: the proximal 80 % (fundus & body/corpus) consisting of acid-
secreting oxyntic gland mucosa, and the reminaing 20 % (antrum) of hormone/gastrin-secreting
pyloric galnd mucosa (Fig. 4-1). The oxyntic gland area is composed of various cell types, namely
surface epithelial, mucous neck, parietal, endocrine and chief cells (Fig. 4-2). Surface epithelial
cells are to produce mucus and bicarbonate. Mucous neck cells secrete soluble mucus, which is
thinner than the visible mucus produced by the surface epithelial cells; these cells also act as stem
cells which are either migrating to the surface to replace the worn-out surface epithelial cells, or
migrating down to become parietal cells. Parietal (Oxyntic) cells produce acid and IF and Peptic
(Chief) cells secrete pepsinogen. Endocrine cells (somatostatin-secreting and histamine-secreting)
are in close proximity to parietal cells and they regulate acid release via a paracrine action.
31
Fig. 4-1. Anatomical and functional parts of stomach Fig. 4-2. Oxyntic gland mucosa showing various cell types
3. Parietal cells and the mechanism of acid secretion
• Secrete HCl at a concentration of 155 mM (pH 0.8)

• Concentrate H+ with three million times higher than that of blood (pH 7)
• Require energy for this process produced by the numerous mitochondria within the cells
• Utilize H+/K+-ATPase to actively pump H+ at the expense of ATP
• Undergo a morphological change during stimulated state for gastric secretion (Fig. 4-3)
Fig. 4-3. Canalicular system in secreting parietal cell Fig. 4-4. Cellular mechanism of acid secretion by the parietal
cell.
(Guyton & Hall’s Medical Physiology, 1996). CA, carbonic anhydrase (Johnson’s Physiology, 2007).
H+ is pumped actively into the lumen while HCO3- diffuses into the blood, giving gastric venous
blood a higher pH than arterial blood (alkaline tide) when the stomach is in active secretion. The
active transport of H+ across the mucosal membrane is catalyzed by H+/K+-ATPase, and H+ is
pumped into the lumen in exchange of K+. Accumulated K+ moves down its gradient across both
membranes via K+ channel. Luminal K+ is therefore recycled by the H+/K+-ATPase. Cl- enters the
cell across the basolateral membrane in exchange of HCO3-. The pumping of H+ allows OH- to
accumulate and form HCO3- from CO2 via carbonic anhydrase (Fig. 4-4).
32
4. Regulation of gastric secretion
Acid secretion is under fine regulation by neurocrine, endocrine and paracrine pathways in a highly
integrated manner. Pepsinogen secretion from the chief cells is usually regulated in parallel
with acid secretion. Basically, acid secretion by the parietal cells is controlled by various cells
located in close proximity to the parietal cells (Fig. 4-5).
4.1. Association of parietal cell with other regulatory cells or mediators
• Enterochromaffin-like cells (ECL cells)

- Located near the parietal cells in the gastric mucosa
- Synthesize histamine (which has H1 and H2 receptors) and mediate acid secretion via H2 receptors
• Endocrine cells (D cells)
- In close proximity to the parietal cells
- Deliver somatostatin in a paracrine fashion to inhibit acid secretion
• Antral G cells (G cells)
- Located in the antrum region of the stomach
- Release gastrin into circulation to stimulate acid secretion
• Prostaglandins from mucosal cells
- inhibit acid secretion in a paracrine manner
• Acetylcholine from nerve cells
- stimulate acid secretion in a neurocrine manner
Fig. 4-5. Schematic representation depicting the relationship of parietal cell and some regulatory cells in the
mediation of acid secretion by the parietal cell. The different intracellular pathways by which the secretagogues
stimulate the generation of H+ ions are omitted. ECL cell: enterochromaffin-like cell; Ach: acetylcholine; PGE:
prostaglandin; H2, histamine receptor type 2; CCK-B: gastrin receptor; M3, muscarinic receptor. Note that the final
pathway of acid secretion depends on the action of H+/K+-ATPase pump.
33
Note: Two related CCK receptors have been identified, CCKA and CCKB. The CCKA receptor’s
affinity for cholecystokinin is three orders of magnitude higher than its affinity for gastrin. Gastrin
binds to a specific parietal cell receptor identified as CCKB receptor.
4.2. Three basic factors and their potentiation effect for acid secretion
• Acetylcholine
• Histamine
• Gastrin
In order to have maximal effect, the three agonists of acid secretion must bind simultaneously on
their specific receptors located in the parietal cell, instead of acting alone. This multiplicative effect
is called potentiation (see Fig. 4-5).
4.3. Regulatory pathways for gastric secretion
• Extrinsic (vagal) nerves

Long reflexes that transmit from the gastric mucosa all the way to the brain stem and then back to
the stomach through the vagal nerves
• Intrinsic (ENS) nerves

Short reflexes that originate locally and are transmitted entirely through the local ENS
• GI peptides
Some peptides, such as gastrin and GRP, stimulate acid secretion while enteric peptides including
secretin, CCK, somatostatin, GIP and enterogastrones inhibit gastric acid secretion and gastric
emptying (Enterogastrones: see Section 6 and Table 4-1).
5. Phases of gastric secretion
Gastric acid secretion is throughout day and night (lowest in the morning and highest in the
evening). Substantial increase in acid secretion occurs after meals whereas secretion between meals
is low (i.e. basal state). Between meals, the emptied stomach contains a relatively small volume of
gastric juice. Its pH is, however, usually less than 2 and the mucosa is acidified. Acidification of
the antral mucosa prevents gastrin release and acidification of oxyntic gland mucosa has an
inhibitory effect on acid secretion. Both of these mechanisms appear to involve the acid-mediated
release of somatostatin from the D-cells via a paracrine action on the gastric antral G cells and
parietal cells. See Next Section “Mediators that inhibit acid secretion”.
During a meal, increase in acid secretion is based on the division of three phases. However, this
division is somewhat artificial because of considerable overlap in regulating acid secretion among
these three phases; in other words, they are not separate but work in concert with each other.
• Cephalic phase
Neural regulation (30% of acid response), as shown in Fig. 4-6.
• Gastric phase
Neural and hormonal regulation (60% of acid response) as shown in Fig. 4-7.
• Intestinal phase
Hormonal regulation (only 10% of acid response; mainly of inhibitory phase).
34
EN
S
ENS
Fig. 4-6. Mechanisms stimulating gastric acid secretion Fig. 4-7. Mechanisms stimulating acid secretion
during the cephalic phase. GRP, gastrin-releasing peptide. during the gastric phase (Johnson’s GI Physiology, 2007).
6. Mediators that inhibit acid secretion
A number of gut peptides, called enterogastrone, are released in response to acid, fatty acid and
hyperosmotic solutions which are physiologically important to inhibit gastric acid secretion and
motility (Table 4-1). Enterogastrone is a substance from the intestine (entero-) that inhibits (-one)
the stomach (gastr-)’s secretion and/or motility. One of the potent inhibitors of acid secretion is the
peptide, somatostatin which is released from the GI endocrine cells (D-cells) of stomach in
response to acid (pH<3). It acts as a paracrine mediator to inhibit acid secretion by parietal cells
and gastrin release by G-cells. Another inhibitor is the peptide secretin which is released from S-
cells in small intestine in response to acid. It acts as a hormone to inhibit acid secretion directly
from parietal cell to large extent, and to inhibit gastrin release from G-cells in a less extent.
Table 4-1. Mechanisms for inhibiting gastric acid secretion.

Site of GI Tract Stimulus Mediators Inhibition of Inhibition of
Gastrin Release Acid Secretion
Antrum Acid Somatostatin ++ +++
(pH < 3.0)
Duodenum Acid Secretin + +++
(Little effect) (Strong effect)
Nervous Reflex +
Hyper-osmotic Unidentified
Solutions Enterogastrone +
Duodenum Fatty GIP + +
and Acids
Jejunum Unidentified +
Enterogastrone
7. The gastric mucosal barrier

The gastric mucosa is under continuous exposure to the erosive action of acid and pepsin. The
gastric pH can fall below 2 for significant periods of time throughout the day. Exposure of mucosal
lining with noxious agents includes the following:
• Endogenous substances: HCl, pepsin
• Ingested substances: high temperature, high osmolarity
35
• Other damaging substance: ethanol, bile acids, drugs (eg. aspirin), and germs (e.g. Helicobacter
pylori).
In view of this fact, effective mechanisms for maintaining mucosal integrity in face of this noxious
environment must be set in place. There are three main gastric defense mechanisms in the gastric
lining, particularly the interaction between mucus and bicarbonate (Fig. 4-8).
• Restitution
• Mucus coating
• Bicarbonate buffering
Buffering by HCO3- and restraint to convective mixing caused by high viscosity of mucus
Fig. 4-8. The gastric mucosal barrier as provided by the HCO3- containing mucus layer. In man, the mucus coat is approximately
0.2 mm thick. Buffering by HCO3- rich secretions of the surface epithelial cells, and the restraint to convective mixing caused by
the high viscosity of the mucus layer, allow the pH at the cell surface to remain near 7, whereas the pH in the gastric juice in the
lumen is 1 to 2 (Berne & Levy’s Physiology, 2008).
Note: When the aggressive factors (e.g. acid, pepsin, H. pylori & aspirin) overwhelm the protective
ones (mucus, bicarbonate & restitution), peptic ulcer disease will ensue. For additional
information on peptic ulcer disease, please see CC of this Lecture.
SUMMARY
• Acid is secreted by the parietal cells which contain the enzyme H+/K+-ATPase on their apical
secretory membranes.
• The three major stimulants of acid secretion are the hormone gastrin, the neurocrine Ach, and
the paracrine histamine, the latter being released from ECL cells in response to gastrin and Ach.
• The gastric mucosal barrier of a normal individual can protect the stomach even in the elevation
of HCl and pepsin levels.
• When HCO3- and/or mucus are suppressed, the barrier is compromised and ulceration may
occur*.
* Further discussion of gastric ulceration, see Tutorial 2 and Lecture 10 & 11)
36
1. Tips on GI Microbiology
For the sake of this GI course, some very basic knowledge of the GI microbiology should be
grasped by the first-year medical students in order to integrate the GI physiology into
pathophysiology.
Peptic ulcer disease (PUD) and Helicobacter pylori

PUD is a general term that refers to ulceration of gastric and duodenal mucosa. While there are
several factors implicated in PUD, colonization of H. pylori is the major cause of pathogenesis,
with 80% of gastric ulcer and 95% duodenal ulcer being attributed to H. pylori infection. See
Clinical Focus on PUD below and Lecture 11.
Gastroenteritis and viral infection

There is a variety of viral infection that may cause gastroenteritis. They include, but are not limited
to, rotarvirus, adenovirus, Norovirus (Norwalk agent). Clinical findings may have watery diarrhea,
vomiting, dehydration and fever etc. Fecal-oral route and/or contaminated foods are the major
transmission. See Case Study below for further discussion.
Diarrhea and bacterial infection

Two types of bacteria that cause cholera and “traveler’s diarrhea” are Vibrio cholerae and
enterotoxigenic E. coli, respectively. Both bacteria can produce enterotoxins, namely cholera toxin
and heat-stable enterotoxin, thus resulting in watery diarrhea. The mechanisms by which V. cholera
and E. coli stimulate intestinal anion and fluid secretion thus diarrhea will be discussed in Section
4.1, Lecture 11, p. 82-84. See also Case Study 1 in Lecture 11, p.87.
Food poisoning and Staphylococcus aureus

S. aureus causes food poisoning associated with foods contaminated by a food handler and stored in
a room temperature where bacteria can multiply and enterotoxin levels increase. Clinical
manifestations include watery diarrhea, vomiting, nausea, abdominal cramps, and etc.
Diarrhea and invasive bacterial infection

Some bacteria such as Salmonella (S. enterica), Yersinia (Y. enterocolitica) and enterohemorrhagic
E. coli cause local intestinal inflammation and thus lead to diarrhea. Clinical observations may
include bloody stools with pus. See Table 11-3 in Lecture 11 (Non-inflammatory vs
Inflammatory diarrhea, p.85).
2. Clinical Focus
PERNICIOUS ANEMIA (PA)
• PA is an autoimmune disease and many patients with PA have antibody-mediated immunity

against their parietal cells that secrete gastric acid and IF. Thus atrophy of the gastric corpus/body
(acid-secreting area) results in achlorhydria (a condition characterized by the absence of acid) and
inability to produce IF. IF is indispensable for B12 absorption in the ileum. Importantly, B12 is
37
important for maturation of RBC in bone marrow and, if deficiency, PA will ensue (For further
information, see Section 2.1 and 2.2 “Absorption of vitamin B12” of Lecture 8&9).
• In contrast, patients with PA have normal gastric antrum (gastrin-secreting area). Thus plasma
gastrin levels of these patients are markedly elevated (i.e. Hypergastrinemia) as a result of the
absence of intraluminal acid, which normally triggers somatostatin-secreting gastric D cells to
inhibit antral gastrin release. Because parietal cells are absent, the elevated plasma gastrin levels are
not associated with enhanced gastric acid secretion.
*For further information, see Section 2.3. “Negative feedback of gastrin and acid” and Table 11-2
of Lecture 11.
• The clinical symptoms of B12 deficiency does not appear over a period of years because B12 can
be stored in liver for several years. Patients with PA develop a megaloblastic anemia in which
the circulating red blood cells are enlarged. Cf. Megaloblast: an abnormally large nucleated
immature RBC that develops in large number in the bone marrow and is plentiful in the circulation
in anemia (see Picture below) associated with deficiency of B12, IF, or folic acid.
• Parenteral (intramuscular) administration of B12 reverses and prevents the manifestations of

PA, but does not influence parietal cells or restore gastric secretion of either IF or acid.
PEPTIC ULCER DISEASE (PUD)
• Parietal cells in the stomach produce acid and are controlled by histamine, acetylcholine and
gastrin.
• Mucosal defense relies upon maintaining an alkaline mucous barrier and a high mucosal blood
flow to rapidly remove hydrogen ions that cross the mucus barrier.
*For further information, see Section 2.1. “Prostaglandins” of Lecture 10.
• PUD, in the form of Duodenal Ulcer (DU) and Gastric Ulcer (GU), is strongly associated with
H. pylori and treatment is directed at eradicating the infection in addition to acid suppression.
*For further information, see Section 1 and 2 on “H. pylori” of Lecture 11.
• Non-H. pylori-associated ulcers may be caused by aspirin or non-steroidal anti-inflammatory
drug (NSAID) usage, hypercalcemia, physiological stress or gastrinoma.
*For further information, see Section 4 “Etiological factors for peptic ulcers” of Lecture 10.
• Gastric ulcers have a malignant potential and should always be biopsied at endoscopy, and
healing following treatment.
38
• Proton pump inhibitors (e.g. ompeprazole) may mask malignant gastric ulcers, so endoscopy is
best performed when this medication has ceased.
• PUD is often associated with anemia, a type of iron-deficiency anemia.
ANEMIA
• Anemia refers to any condition in which there is an abnormally low hemoglobin concentration
and/or red blood cell count.
• The most common type is iron-deficiency anemia, caused by a deficiency of iron, which is an
essential component of the hemoglobin molecule.
• Aplastic anemia is anemia due to destruction of the bone marrow, which may be caused by toxic
chemicals, ionizing radiation, or some antibiotics.
• Compare with PA-induced anemia (see above).
3. Case Study
A medical student presents to the emergency room with a two-day history of acute sign and
symptoms characterized by severe nausea and vomiting. He admits that he ate a lot of sushi and
shellfish during a buffet dinner three days ago. He has been unable to keep down any fluids and
says that he is weak and dizzy (especially when he stands up). Serum electrolytes are drawn
showing hypokalemia (low K+), hypochloremia (low Cl-), and the presence of metabolic
alkalosis.
Resolution: Viral Gastroenteritis
• These abnormalities arise from two sources. First, the loss of gastric juices, rich in H+, K+, and
Cl-, accounts for a major part of the metabolic disturbance, especially since the student is unable to
replace them orally.
• These are ions secreted by parietal cells via the transport processes present in the luminal or
canalicular membrane. The metabolic abnormalities are further exacerbated by the student’s
dehydration. The contraction of vascular volume activates renal mechanisms important for
preserving volume. As a consequence, water and Na+-bicarbonate are reabsorbed at the cost of
urinary K+ and H+ excretion.
• Loss of fluid or hypovolemia leads to weakness and dizziness, symptoms accountable for
orthostatic or postural hypotension.
• Metabolic alkalosis is due to loss of gastric juice containing H+ ions.
• Vomiting is a self-defensive mechanism (also diarrhea in other cases).
• Oral rehydration solution (ORS) is the most effective as well as cost effective treatment (see
Section 4.3, Lecture 7 and Section 4.3, Lecture 11).
• Speculate what specific causative agent may be involved in this patient.
39
LECTURE 5: Salivary and Pancreatic Physiology
Learning objectives
• Describe the function and regulation of salivary secretion or saliva
• Understand the function and regulation of exocrine pancreatic secretion
• Understand the mechanism of pancreatic ductal HCO3- secretion by secretin
• Correlate this basic knowledge of pancreatic secretion with its clinical relevance
1. Salivary secretion
Saliva is always hypotonic to plasma, having less Na+ and Cl- but more K+ and HCO3-.
• Salivary juice
- Water, inorganic and organic components
• Functions of saliva
- Digestion (a-amylase, lingual lipase) - Solubilization of food for taste bud
- Lubrication of food for swallowing - Cleaning of buccal mucosa and teeth
- Protection (lysozyme or IgA) - Facilitation of speech
*The functional importance of saliva is illustrated by the problems encountered in individuals with
xerostomia (a hypofunction of the salivary gland or dry mouth), which is accompanied by
hypofunction of the lacrimal glands); dry mouth is susceptible to infection & dental caries.
1.1. Salivary glands and their structure

• Parotid glands - entirely serous (watery)
• Sublingual - largely mucous
• Submandibular - mixed
1.2. Salivon
The functional unit of salivary gland is called salivon (Fig. 5-1).
• Acinar cells (serous and mucous) • Intercalated duct
• Striated duct • Myoepithelial cells
Fig. 5-1. Diagram showing the functional histology of the salivon, the secretory unit of the salivary gland (Johnson’s
GI Physiology, 2007).
40
2. Regulation of salivary secretion

- In contrast to other secretory glands, GI hormones have no significant role in salivary secretion
- Exclusively under neural control, i.e. ANS (Fig. 5-2).
- Parasympathetic nerves exert major stimulatory effect
- Sympathetic nerves also stimulate secretion
- Aldosterone and ADH modify the ion content of saliva by decreasing Na+ and increasing K+, but
they do not regulate the secretion
Fig. 5-2. Regulation of the salivary glands by the central nervous system.
3. Pancreatic secretion
The pancreas produces more than 1 L/day of exocrine secretions, and also secretes the endocrine
hormones. The exocrine tissue (98% of total pancreatic mass) secretes an aqueous component
containing HCO3- for neutralization of gastric acid chyme and a mixture of enzymes for food
digestion.
3.1. Basic structure of the pancreas

• Endocrine portion
- Pancreatic islets: insulin (β-cell), glucagon (α-cell), pancreatic polypeptide (PP-cell) and
somatostatin (δ-cell)
• Exocrine portion - Acinar cells & duct cells
• Blood vessels
• Extracellular space
____________________________________________________________
Pancreatic cell type Relative volume occupied (%)_
Acinar 82.0
Duct 3.9
Endocrine 1.8
Blood vessels 3.7
Extracellular space 9.4
__________________________________________________________________
Table 5.1. Volumes occupied by various cellular elements in guinea pig pancreas.
Data from Bolender RP: J Cell Biol 61:269, 1974.
3.2. Duct system of the exocrine pancreas

The structure of the exocrine pancreas resembles that of the salivary glands. The pancreas contains
blinded ended tubules that are surrounded by polygonal acinar cells and are organized into lobules,
called acini. The tiny ducts that drain the acini are called intercalated ducts. The intercalated ducts
41
empty into larger intralobular ducts. All of the intralobular ducts of a particular lobule then drain
into a single extralobular duct; this duct in turn empties into still larger ducts. These larger ducts
converge into a main duct (pancreatic duct) that enters the duodenum along with the common bile
duct (Fig. 5-3).
Fig. 5-3. Pancreatic duct system of the pancreas (Berne & Levy’s Physiology, 2004).
4. Pancreatic juice
Two components of pancreatic juice
• Aqueous component
- Secreted by pancreatic ductal epithelium
- Na+ and HCO3- for neutralization
• Enzymatic component
- Secreted by pancreatic acinar cells
- Principal enzymes for major foodstuff digestion (Table 5-2)
4.1. Secretions from acinar cells
Table 5-2. Proteins of human pancreatic juice.

Protein Molecular Mass proportion
Weight (%)
a-Amylase 54,800 5.3
Pancreatic lipase (Triacylglycerol hydrolase) 50,500 0.7
Phospholipase A2 17,500 -
Colipase 1 - -
Colipase 2 - -
Procarboxypeptidase A1 46,000 16.8
Procarboxypeptidase A2 47,000 8.1
Procarboxypeptidase B1 47,000 4.4
Procarboxypeptidase B2 47,000 2.9
Trypsinogen 1 28,000 23.1
Trypsinogen 2 26,000 -
Trypsinogen 3 26,700 16.0
Chymotrypsinogen 29,000 1.7
Proelastase 1 30,500 3.1
Proelastase 2 30,500 1.2
Data are from Scheele G et al: Gastroenterololgy 80:461, 1981.
42
Serum a-amylase and lipase are the most commonly used blood tests to diagnose or exclude acute
pancreatitis (AP). Both enzymes are released in large quantities into the circulation during acute
inflammation of the pancreas. Upon an AP attack, serum amylase can be raised from its normal
value (100-300 IU/L) up to more than ten folds.
*For additional information on AP, please see Case Study of this Lecture.
4.2. Cellular mechanism for HCO3- secretion by pancreatic duct cell

In this model, the Na+/K+-ATPase located at the basolateral membrane of duct cell creates an
electrochemical gradient of Na+ to move into the cell in exchange of H+. There is some evidence
that an H+-ATPase may actually pump H+ out of the cell. In either case, CO2 diffuses readily into
the alkalinized cell, combining with water to form HCO3-. This latter step is catalyzed by carbonic
anhydrase (CA). The combined movement of H+ across the basolateral membrane leads to a
building up of HCO3- and the movement of HCO3- across the apical membrane in exchange of for
Cl-. As H+ leaves the cell, it combines with HCO3- in the plasma to produce more CO2, which is
free to diffuse into the cell (Fig. 5-4). Because of this secretory process, venous blood from the
actively-secreting pancreas has a lower pH than blood from a non-secreting gland. The rate of
HCO3- secretion depends on luminal Cl- and the activity of Cl- channel, called Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) in the apical membrane. The conductance of
CFTR is activated by cAMP in response to stimulation by secretin and it is present in ductal cells,
but not in acinar cells. This channel occurs in many epithelial cells (pancreatic, airway and
intestinal) and its defective regulation causes cystic fibrosis. In the pancreas, the defect results in
thick acinar secretions (mucus), which blocks the duct and destroys the gland, and thus finally
leading to pancreatic exocrine insufficiency (see CC of this Lecture).
cAMP
(via electrical gradient)
Fig. 5-4. Cell model for the secretion of bicarbonate by the pancreatic duct cell (Johnson’s GI Physiology, 2007).
5. Three basic factors that stimulate pancreatic secretion

• Acetylcholine
- released from vagal nerve endings and from cholinergic nerves in the ENS (neurocrine) to
stimulate acinar cells to secrete enzymatic component
• Cholecystokinin
- released from duodenal and upper jejunal mucosa (endocrine “I” cells), when food (notably fat)
enters the small intestine to stimulate acinar cells to secrete enzymatic component
• Secretin
- released from intestinal mucosa (endocrine “S’ cells), when highly acidic food enters the small
intestine to stimulate duct cells to secrete aqueous component
43
6. Phases of pancreatic secretion
Regulation of each phase involves endocrine and parasympathetic nervous pathways.
• Cephalic phase
- 20% of pancreatic secretion in enzymatic component, as shown in Fig. 5-5.
Thought of food or feeding directly stimulates acinar cells via acetylcholine release.
• Gastric phase
- 5% of pancreatic secretion
Food in the stomach stimulates gastrin release and also causes increased vagal activity to acinar
cells.
• Intestinal phase
- 75% of pancreatic secretion in both enzymatic & aqueous components (Fig. 5-6).
An acid of pH<3.5 in duodenum stimulates releases of secretin from the duodenal epithelium (S-
cells) into blood and this stimulates release of the aqueous component by the duct cells. The HCO3-
neutralizes the acid and, at pH>4.5, secretin production is inhibited. The products of protein and fat
stimulate release of CCK from other duodenal epithelium cells (I-cells). CCK is a powerful
stimulant of enzymatic component released by the acinar cells. Of note, the action of secretin
(released in small amount as hormones) on the duct cells is magnified by the potentiation of CCK
and ACh, as shown in dashed lines of Fig. 5-6.
Fig. 5-5. Mechanisms involved in the stimulation Fig. 5-6. Mechanisms involved in the stimulation of
pancreatic
of pancreatic secretion during cephalic phase. secretion during intestinal phase. Dashed lines indicates
potentiation
Dashed lines are of little importance in man. with secretin (Johnson’s GI Physiology, 2007)
SUMMARY
• Regulation of salivary secretion is unique in two respects of GI physiology: firstly, salivation is

practically under exclusive control of the ANS, but not hormones; secondly, both
parasympathetics (major one) and sympathetics stimulate salivary secretion.
• Pancreatic secretion consists of an aqueous HCO3- component from the duct cells and an
enzymatic component from the acinar cells.
• 3 major stimulants of pancreatic secretion are cholinergic ACh and hormones CCK & secretin.
• Primary mediator of aqueous component is secretin whose effects are potentiated by CCK/ACh.
• Abnormal pancreatic secretion (pancreatic insufficiency) occurs in such diseases as pancreatitis,
cystic fibrosis, and pancreatic cancer that involve the gland itself.
44
1. Clinical Focus
CHRONIC PANCREATITIS (CP)
• CP is a chronic inflammatory condition of the pancreas resulting in pancreatic exocrine and/or

endocrine insufficiency
• Pain, steatorrhea, maldigestion, and diabetes mellitus (DM) are the main clinical features of
CP. Maldigestion occurs when the pancreas fails to produce sufficient digestive enzymes to
hydrolyze dietary nutrients (notably lipase thus steatorrhea), and finally leading to weight loss.
Glucose intolerance is common in CP and progresses to diabetes (insulin deficiency) in later
stages as pancreatic islets are destroyed.
• Alcohol is by far the commonest etiological factor. Other causes include repeated attack of AP,
hereditary, cystic fibrosis and idiopathic origins
• In contrast to AP, serum amylase or lipase levels may be normal in CP. Instead, a combination
of tests of functional and anatomical assessments is useful. Functional test includes secretin
stimulation test (bicarbonate production) and CCK stimulation test (enzymatic production).
• Steatorrhea and maldigestion can be managed by pancreatic enzyme replacement; DM may

require insulin injection.
*For basic concept of digestion and absorption of nutrients, see Lecture 7 and Lecture 8&9.
CYSTIC FIBROSIS (CF)
• CF is the most common lethal genetic disorder of Caucasians and causes pancreatic
insufficiency. The genetic basis is involved in a defective gene called the cystic fibrosis
transmembrane regulator (CFTR). The CFTR gene encodes for a membrane protein, which is
cAMP-regulated Cl- channel, and which is mainly involved in pancreatic and pulmonary functions.
The most common mutation of CFTR involves deletion of three nucleotides encoding
phenylalanine at position 508.
• In the pancreas, pancreatic insufficiency resulting from CF causes maldigestion and

malabsorption of nutrients (see Clinical Note “Steatorrhea”, Lecture 8&9, p.73). In addition to
the loss of pancreatic enzyme output (due to acinar cell destruction), inadequate bicarbonate
secretion by the duct cells results in failure to adequately neutralize the pH of gastric chyme.
• CF can be clinically assessed by “Sweat Test”, by which, with drug stimulation (e.g.
pilocarpine), the sweat gland of CF patients produces higher (3-6 times) concentrations of Na+ and
Cl- compared with normal subjects.
45
2. Case Study
A 70-year-old man is admitted to the surgical ward of PWH with sudden onset of epigastric (upper
abdomen) pain for 12 hours. His serum a-amylase levels are found to be 3,000 IU/L (Normal range:
100-300 IU/L). A computerized tomography scan (CT imaging is most useful in visualizing the
pancreas, as overlying bowel gas can impair the view obtained at ultrasound) is performed which
shows a swollen pancreas with edema around the pancreas. Later on, this patient starts to have
difficulty in breathing and his oxygen saturation drops to 87%, and his respiratory rate is 30/min,
indicative of respiratory failure/systemic complication.
Resolution: Acute Pancreatitis (AP)
• AP is characterized by an acute inflammatory reaction in the pancreas which results in an abrupt

onset of severe upper abdominal pain. There is acinar damage with digestive enzyme leak (e.g. a-
amylase and lipase), which results in autodigestion and microcirculatory changes and perhaps, more
importantly, the lethal AP-induced systemic inflammatory response syndrome (SIRS) and multi-
organ dysfunction syndrome (MODS).
• The major etiologic factors of AP are gallstones and alcoholism, which accounts for 80% of all
cases.
• Premature activation of trypsinogen to trypsin inside the pancreas is thought to be an important

step of AP, which may be caused by biliary stones, alcohol, drugs and infections.
• Raised serum amylase and lipase levels are usually the clinical test for the diagnosis of AP.
Amylase tends to be cleared most rapidly from the serum and is the first enzyme to fall during
resolution of AP. If a patient presents more than a few days after onset of abdominal pain, serum
amylase can be normal or only slightly elevated. Serum lipase is, however, cleared less rapidly, so
this enzyme is more likely to remain elevated in patients whose onset of symptoms is several days
earlier. In addition, serum amylase levels can be elevated in non-AP conditions such as
pancreatic duct obstruction, pancreatic cancer, appendicitis, bowel obstruction and renal
failure.
• Patients with mild AP (80% of cases) are monitored routinely and are treated with intravenous
fluids and analgesia, and are kept nil by mouth. This approach usually ensures a full recovery.
• Patients with severe AP, e.g. SIRS and MODS, are monitored under careful intensive care unit.
• Repeated attacks or episodes of AP can lead to chronic pancreatitis, which may result in
pancreatic insufficiency.
46
LECTURE 6: Hepatobiliary Physiology
Learning objectives
• Appreciate the regulation and functional importance of the hepatobiliary system
• Distinguish the physical properties of organic constituents of bile acids
• Understand the solubility of bile acids and its physiological significance
• Appreciate the significance of enterohepatic circulation of bile acids
• Describe the function and regulatory mechanism of gallbladder
• Apply this basic knowledge to the hepatobiliary dysfunction
1. The liver
It is one of the largest organs (~1.5kg) located in the upper right portion of the abdomen. The
functions of the liver are far more diverse and serve as a chemical factory, an excretory system, an
exocrine gland, and an endocrine gland; they include, to name but a few:
• Endocrine, e.g. Angiotensinogen

• Clotting, e.g. Fibrinogen
• Plasma proteins, e.g. Albumins & globulins (plasma oncotic pressure)
• Metabolic functions, e.g. carbohydrate, fat & protein metabolism
• Storage of irons and vitamins, e.g. B12, A and D
• Excretion & degradation, e.g. steroids & other hormones; drugs & toxins
• Exocrine bile secretion that is related to digestion
1.1. Basic anatomy of the liver
• Two lobes (right and left)

• These two lobes function independently
• Blood supply from 2 sources:
Portal veins (80%) & hepatic arteries (20%)
• Basic functional unit, called the liver lobule
• 50,000 to 100,000 individual lobules
The liver lobule is composed of many hepatic cellular plates; two of which are shown in Fig. 6-1.
They radiate centrifugally from the central vein, like spokes in a wheel, to form the venous
sinusoids. Each hepatic plate is usually two-cell thick of hepatocytes and between the adjacent cells
lying small bile canaliculi that empty into bile ducts.
In addition to the hepatic cells, the venous sinusoids are lined by Kupffer cells (KC), which
provide a filtering mechanism by removing bacteria, foreign matter, and aging red blood cells. The
KC constitutes 80-90 % of the fixed macrophages of the reticuloendothelial system (RES).
47
Fig. 6-1. Basic structure of a liver lobule, showing the hepatic cellular plates, the blood vessels, the bile-collecting system, and
the lymph flow system (Guyton & Hall’s Physiology, 2000).
2. Bile
- One of the many functions of the liver is to secrete bile

- It secretes between 600 and 1,200 ml/day and serves two important functions:
2.1. Bile functions

• As an important role in fat digestion and absorption
- to emulsify the fat particles into smaller ones that can be attacked by lipase
- to aid in absorption of the digested fat to and through the intestinal mucosal membrane by
forming soluble micelles with the fat
• As a means for excretion of wastes from the blood, e.g. bilirubin, excess of cholesterol, or drugs
2.2. Constituents of bile

The problem of fat insolubility in GI lumen is solved by the constituents of bile. Bile is a complex
mixture of inorganic and organic components, the physical properties of which account for the
ability of bile to solubilize normally insoluble fat digestion product.
In fact, the bile itself contains molecules that are insoluble in water but that are solubilized in bile
because of the interactions of its various organic constituents, i.e. Amphipathic properties:
hydrophilic and hydrophobic.
- Inorganic and organic components

- Inorganic component consists of water and electrolytes
- Physical properties of organic components account for the ability of bile to solubilize fat
See Fig. 6-2.
2.3. Organic components

Bile acids or bile salts are the most major component of organic bile, which are the derivative of
cholesterol (carboxylic acids); bile pigments (tetrapyrroles) that are related to porphyrins.
• Bile acids (70%)

• Phospholipids (primarily lecithins, 20%)
• Cholesterol (4%)
• Bile pigments (mainly bilirubin, 2%) derived from aging RBCs.
48
Cholesterol nucleus
Fig. 6-2. Structures of components of micelles and micelles themselves. (A). Representations of bile salts, lecithin, and
cholesterol molecules, illustrating the separation of polar and non-polar surfaces. (B). Cross-section of a micelle, showing the
arrangement of these molecules plus the principal products of fat digestion. Micelles are cylindrical disks whose outer curved
surfaces are composed of bile salts (Johnson’s Essential Medical Physiology, 1992).
2.4. Forms of bile acids
The liver synthesizes two bile acids, cholic and chenodeoxycholic acids (primary bile acids);
within the gut lumen, a fraction of each is dehydroxylated by bacteria to form deoxycholic acid
and lithocholic acids (secondary bile acids) (Fig. 6-3). All these bile acids (primary plus
secondary) are returned to the liver from the portal blood and secreted into bile. The solubility of
the bile acids depends on the number of hydroxyl groups present and the state of the terminal
carboxyl group. Cholic acid, with three hydroxyl groups, is the most soluble whereas lithocholic, a
monohydroxy acid, is the least soluble. Bile salts are also present in conjugated forms; each bile
acid may be conjugated in the liver with the amino acid glycine or taurine, yielding a total of eight
bile salts. The bile acids are named for the parent bile acid and the conjugating amino acid (e.g.
tauro-cholic acid, glyco-lithocholic acid). The conjugated bile acids exist as salts of various cations,
primarily sodium, and are referred to as bile salts. The purpose of conjugation of bile acids to bile
salts within the liver is to decrease the pK of the compounds, thus making them more soluble in the
aqueous solution of the intestinal lumen. It is because the duodenal contents have a pH of 3-5. The
bile acids have a pK of approximately 7. Thus most bile acids are present in their non-ionized
forms which are water insoluble in this range of duodenal pH. However, bile salts have a pK of 1-4
and, consequently, bile salts are present in their ionized forms, which are water soluble at duodenal
pH. Physiologically, this conjugation increases the detergent and micellar-forming properties
of bile acids and minimizes their uptake in the upper intestine. On the other hand, conjugated
bile salts are subject to de-conjugation (i.e. removal of the peptide bonds of the conjugating amino
acids) and de-hydroxylation (i.e. removal of the hydroxyl groups) by gut bacteria within the
intestine. By doing so, the water solubility decreases (or fat solubility increases) so as to enhance
their reabsorption by the distal ileum via enterohepatic circulation (see Section 3 below).
49
Fig. 6-3. Principal organic constituents of bile and various forms of bile acids. The two primary bile acids may be converted to
secondary bile acids in the intestine. Each of the four bile acids may be conjugated to either glycine or taurine to form bile salts.
The R-groups of lecithin represent fatty acids (Johnson’s Essential Physiology, 1992).
3. Significance of the enterohepatic circulation of bile acids

Unlike the pancreas whose secretions are controlled by intestinal hormones, bile salt secretion is
controlled by the concentration of bile acids in the blood. The rate at which bile acids return to
the liver has a major influence on their rate of synthesis and secretion. The return of bile acids
negatively feedback-inhibits the biosynthesis of new bile acids (via 7 a-hydroxylase, the rate-
limiting enzyme for bile acid synthesis from cholesterol), while stimulating high rates of secretion.
Bile secretion depends on the total bile acid pool (~ 2.5g) in the body distributed in liver,
gallbladder, bowel and blood, i.e the pool. The movement of bile acid pool from this liver-gut-
liver axis is termed the enterohepatic circulation (Fig 6-4). Bile acids are transported from the
lumen of the intestine into portal blood on a Na+-bile acid co-transporter located in the terminal
ileum. In this way, 95% of bile acids are re-circulated to the liver instead of being excreted;
approximately 20% of the pool is excreted in the feces each day and is replenished by hepatic
synthesis of new bile acids. The entire pool may be re-circulated twice in a typical meal and as
many as five times in a high-fat meal.
• Return of bile acids through enterohepatic circulation
- Amount absorbed from the terminal ileum
- In turn, depends on the digestive state
• Bile acids newly synthesized in the hepatocytes
- Inversely correlated with the bile acid return via the portal blood
- Return of BA inhibit, via negative feedback, 7 a-hydroxylase, the rate-limiting enzyme for BA
synthesis from cholesterol
50
Fig. 6-4. Representation of key components of the enterohepatic circulation of bile acids in normal humans. Bile is dumped into
the duodenum by contractions of the gallbladder. In the small intestine, bile acids first emulsify dietary fat and form mixed
micelles with the products of fat digestion. In the terminal ileum, bile acids are reasorbed. Bile acids return to the liver in the
portal blood, where they are avidly taken up by hepatocytes and resecreted into bile (Berne & Levy’s Physiology, 2004).
About 20% of the total bile acid pool is excreted into the feces and must be replaced, which is the
only significant mechanism of cholesterol excretion. Treatment with drugs (e.g. Cholestyramine)
that block the reabsorption of bile acids in the ileum promotes the synthesis of new bile acid from
cholesterol. These drugs can be used to lower the levels of cholesterol in the blood (see CC, p.55).
4. Gallbladder
Between meals, bile is stored in the gallbladder where water and salts are extracted. This action is
to concentrate the bile acids (5-10 folds), which increases their ability to form micelles and thus aid
fat digestion and absorption. Bile is expelled in response to CCK into the duodenum shortly after
the start of a fatty meal.
4.1. Gallbladder function

• Storage of bile
• Concentration of bile
• Expulsion of bile
Note: Removal of the gallbladder (cholecystectomy) does not affect normal digestion and
absorption in individuals because of treatment of gallstones. Without the gallbladder, bile is
released continuously into the duodenum from the liver. However, the overall secretion of bile in
response to a meal is somewhat reduced. In fact, gallbladder is naturally absent in some animals
such as the rat and horse.
4.2. Composition of bile

Generally, the gallbladder epithelium greatly concentrates the organic constituents of bile while
there is a net decrease in osmolality in spite of actively absorbed Na+ ions (see Table 6-1).
Table 6-1. Value for major components of liver and gallbladder bile
51
Component Liver bile Gallbladder bile

Na+ (mmol/L) 150 300
Cl- (mmol/L) 80 5
K+ (mmol/L) 5 10
Bile salts (mmol/L) 30 315
Lecithin (mmol/L) 0.5 4
Cholesterol (mg/100ml) 110 600
Bilirubin (mg/100ml) 100 1000
4.3. Regulatory mechanism of gallbladder emptying

Regulation of gallbladder is controlled by the contraction of the gallbladder smooth muscle and
relaxation of the sphincter of Oddi in response to the hormone CCK within 30 minutes of
ingestion of a meal. In addition, increased vagal activity can increase, to a lesser extent, the
contraction of the gallbladder and relaxation of sphincter of Oddi, which leads to the emptying of
bile into the duodenum (Fig. 6-5).
• Bile acids
- Bile acids that return to the liver via portal circulation inhibit bile synthesis and stimulate bile
secretion
• Secretin
- Stimulate water and HCO3- secretion
• CCK
- Stimulate contraction of gallbladder and relax Sphincter of Oddi
• Vagus
- Little or no effect on bile secretion but minor effect on gallbladder contraction
Fig. 6-5. Regulation of bile flow between periods of digestion. A. During interdigestive period. B. During digestive period.
5. Bilirubin formation and excretion

Bilirubin is the most major bile pigment produced by breakdown of either hemoglobin or
myoglobin in the reticuloendothelial system (RES). This is an important process to eliminate the
end product of hemoglobin degradation (Fig. 6-6).
- RBC dies after 120-day life span
- Hemoglobin released and taken up by tissue macrophages (liver RES)
- Broken down into globin and heme
- Heme open to release iron & the remaining porphyrin ring is converted into bilirubin
52
Fig. 6-6. Formation and excretion of bile pigment (Johnson’s GI Physiology, 2007).
Hepatocytes extract bilirubin from the blood and conjugate it to glucuronic acid, by means of a
hepatic enzyme called glucuronyl transferase, to form water-soluble bilirubin glucuronide. It is
then secreted into the bile and is partially responsible for its golden color. Since it is water-soluble,
it does NOT take part in micelle formation. Bilirubin glucuronide is deconjugated and reduced to
urobilinogen by bacteria of the small bowel, which is excreted in the form of stercobilin into
feces. Some urobilinogen is absorbed into the systemic circulation, where it is filtered by the
kidneys and excreted in the form of urobilin into urine.
The most common disorders in hepatobiliary system are jaundice and gallstones (pigment and
cholesterol stone). The causes of jaundice are (1) increased destruction of RBC; (2) obstruction of
the bile ducts; (3) liver impairment. A failure to clear sufficient bilirubin by the liver results in
elevated blood levels of conjugated and/or unconjugated bilirubin, thus leading to the yellow
appearance of the skin and eyeballs, the condition known as jaundice.
Physiological jaundice is due to high plasma levels of bilirubin in otherwise healthy neonates.
This type of jaundice may be caused by rapid fall in blood hemoglobin that normally occurs
at birth. It can be treated by exposure to blue light, which makes bilirubin more soluble in plasma
without having to be conjugated with glucuronic acids. *For additional information on jaundice,
please see Clinical Focus of this Lecture.
Unconjugated bilirubin, such as the defect in liver glucuronyl transferase, may lead to the
precipitation of unconjugated bilirubin in the form of calcium salt, called pigment stone. On the
other hand, altered hepatic bile composition, such as enhanced cholesterol that is more than can be
solubilized in micelles, may lead to cholesterol stone.
SUMMARY
• Bile is secreted by the liver as complex mixtures of bile acids, phospholipids, cholesterol, bile
pigments, electrolytes and water
• Primary bile acids are synthesized from cholesterol by the liver cells and conjugated to taurine
and glycine
• In the intestine some bile acids are deconjugated, and some are dehydroxylated to form secondary
bile acids
• Bile secretion depends primarily upon the secretion of bile acids, which in turn depends upon
liver uptake of bile acids from the portal blood and on bile acid synthesis
• Disorders in hepatobiliary system may lead to, at least, two clinical manifestations, namely
jaundice and gallstones (pigment and cholesterol stones).
53
1. Tips on GI Pharmacology
For the sake of this GI course, some very basic knowledge of the GI pharmacology should be
grasped by the first-year medical students in order to integrate the GI physiology into
pathophysiology.
Drugs used for PUD

Antacids: e.g. sodium bicarbonate, aluminum hydroxide, and magnesium hydroxide.
H2 receptor antagonists: e.g. cimetidine (Tagamet), ranitidine (Zantac), and famotidine (Pepcid).
Muscarinic Ach receptor antagonists: e.g. pirenzepine and propantheline.
H+/K+-ATPase inhibitors: e.g. omeprazole (Losec, Prilosec) and lansoprazole.
Antibiotic regimens: e.g. Amoxycillin and clarithromycin or tetracycline and metronidazole
regimens. See “Triple Therapy” in Lecture 11, p.81.
Drugs used for diarrhea

Intravenous infusion of saline.
Oral rehydration therapy: ORS (see Section 4.3, Lecture 7 and Section 4.3, Lecture 11)
With or without antibiotic therapy.
Anti-diarrheal drugs: Loperamide.
Drugs used for UC and CD

Anti-inflammatory drugs:
NSAIDs (Sufasalazine and 5-aminosalicylic acid) and corticosteroids (Prednisone). See Case
Study of this Lecture.
Drugs used for hypercholesterolemia

Cholestyramine: see Figure 6-4 and Clinical Note of this Lecture.
Ezetimibe: it is an inhibitor of intestinal absorption of cholesterol.
Statins: Lovastatin (Mevacor), Simvastatin (Zocor) and Pravastatin (Pravachol).These drugs are inhibitors
of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). HMG-CoA reductase is an
enzyme that catalyzes the rate-limiting step in cholesterol synthesis (HMG-CoA mevalonate).
Niacin: it is a vitamin that decreases production of LDL leading to a decrease in LDL and an
increase in HDL levels.
2. Clinical Note
ILEAL DISEASE OR RESECTION
Crohn’s disease (CD) is an inflammatory bowel disease that affects the ileum. The first-line
treatment is NSAIDs and followed by glucocorticoids; the final option is the removal of the
inflamed ileum or ileal resection (see CC in Lecture 1). Ileal resection results in bile acid
malabsorption (see Section 3 of this Lecture on “Enterohepatic circulation of bile acids”). Bile acids
then enter the colon and stimulate colonic Cl- secretion, concomitantly with Na+ and water loss, thus
54
producing a secretory diarrhea, which is mediated by an cAMP-dependent mechanism. With

increased fecal bile acid losses, hepatic synthesis is increased to compensate. If the ileal
disease or resection is severe or extensive, the bile acid loss may exceed the capacity of the
liver to compensate and thus malabsorption of dietary fat and fat soluble vitamins ensues.
Note: Ileal resection may also result in vitamin B12 deficiency (see Case Study below).
BILE ACID SEQUESTRAT
• Cholestyramine
This drug can act as a resin that promotes the excretion of bile salts by forming an insoluble
complex in the small intestine. By doing so, it leads to an increase in the conversion of cholesterol
into bile, LDL receptors in the liver and catabolism of LDL and thus it can act as a lipid-lowering
drug. Clinical use: Type IIa and IIb hyperlipidemia. Side effects: steatorrhea, stomach pain, and
deceased absorption of fat soluble vitamins. In addition to acting as a lipid-lowering drug,
cholestyramine is a water-insoluble cationic resin that binds bile acids in the intestinal lumen.
When bile acids are bound to the resin, they cannot stimulate colonic Cl- secretion or cause
secretory diarrhea (see Case Study below).
3. Clinical Focus
Jaundice
• This clinical condition is characterized by a yellow staining of the tissues produced by high blood
levels of total bilirubin, either free (unconjugated) or conjugated bilirubin, i.e. hyperbilirubinemia
(Normal value <17 µmol/L). Jaundice associated with high levels of conjugated bilirubin in adults
may occur when bile excretion is blocked by gallstones (post-hepatic or obstructive jaundice).
• Jaundice associated with high levels of conjugated and/or unconjugated bilirubin is caused by
some disorders of liver cells at the stages of uptake, conjugation or secretion of bilirubin (intra-
hepatic jaundice), as observed in some liver diseases, e.g. liver cirrhosis, hepatitis or glucuronyl
transferase (GT) deficiency.
• Since free bilirubin is derived from heme, jaundice associated with high levels of free bilirubin is
usually caused by an excessive rate of hemolysis (pre-hepatic jaundice). This is the cause of
jaundice in infants who suffer from erythroblastosis fetalis; a type of hemolytic anemia that occurs
as a result of maternal-fetal blood group incompatibility.
• Physiological jaundice of the newborn is due to high levels of free bilirubin in otherwise healthy
neonates. This type of jaundice may be caused by the rapid fall in blood hemoglobin concentrations
that normally occurs at birth. In premature (pre-term) infants, it may be caused by inadequate
amounts of hepatic enzymes that are needed to conjugate bilirubin so that it can be excreted in the
bile.
• Treatment of physiological jaundice is done through phototherapy in neonates. Exposure to light

results in photoisomerization of unconjugated bilirubin with disruption of the internal hydrogen
bonding, which increases water solubility and elimination of these isomers in the bile and urine.
55
4. Case Study
4.1. Case study
A 50-year-old woman presents with five-month history of yellowing coloration of sclera with
increasing severity. She also has itchiness of skin (pruritus) for the past few weeks. Her urine is
found to be very dark but her stool turns out to be pale. Her plasma levels of conjugated
bilirubin are considerably raised. A typical liver function test shows elevated plasma alkaline
phosphatase (ALP) levels while alanine/aspartate aminotransferase (ALT/AST) and albumin levels
are normal or minimally deranged in this patient. An ultrasound scan shows a dilated common bile
duct.
Resolution: Obstructive Jaundice
• This is a typical case of obstructive or post-hepatic jaundice (see classification of jaundice above).
• Yellowish sclera is due to deposit of excess bilirubin in the eye; dark urine and pale stool are
attributed to the different amount of bilirubin secreted in the urine and stool, respectively.
• Common causes include bile duct stones and pancreatic head cancer (see CC, Lecture 8&9,
p.73). Other possibilities are narrowing of the bile ducts (bile duct strictures) or other cancers like
cancer of the bile ducts or duodenum.
• In prehaptic jaundice: ALT/AST & ALP are normal; in posthepatic jaundice: ALP is elevated
with dark urine and pale stool; in hepatic jaundice: ALP, AST/ALT are elevated. Also compare
with other biochemical indicators of hepatic function.
4.2. Case study
A 40-year-old man was diagnosed with Crohn’s disease. For the past 10 years, he was treated
medically with anti-diarrheal drugs and anti-inflammatory drugs, including glucocorticoids. During
that time, he has several episodes of spontaneous remissions. He had finally an option to undergo
surgery and 80% of his distal ileum was removed (ileal resection). After the surgery, he has
diarrhea. His stools are oily, pale, and foul-smelling. His doctor prescribes him with cholestyramine
to control his diarrhea. Despite this, he continues to have steatorrhea and needs to take monthly
injections of vitamin B12.
Q1. Why was the patient put on gluccorcorticoid treatment?

Q2. Why does the patient have steatorrhea after his ileal resection?
Q3. Explain what type of diarrhea he has.
Q4. How does cholestyramine control his condition of diarrhea?
Q5. Why does he need to receive monthly injection of vitamin B12? What additional conditions can
lead to vitamin B12 deficiency (Hint: see Section 2.1 & 2.2, Lecture 8&9)?
56
LECTURE 7: Digestion and Absorption I
Learning objectives
• Appreciate the structural modifications and basic principles of intestinal absorption
• Understand the basic principle of digestion and absorption of carbohydrates
• Understand the basic principle of digestion and absorption of proteins
• Discuss their malfunctions and their clinical implications
1. Introduction
Energy is derived from food, predominantly in the form of carbohydrates and fat. The diet also
provides essential amino acids, necessary for protein synthesis. Carbohydrates, fat and protein are
macromolecules that must be digested to a simpler form before they can be absorbed across the
intestinal epithelium. This is a complex process. Digestion begins with the action of salivary
amylase on starch, gastric lipase on fat, and hydrochloric acid and pepsin on protein that, in the
presence of forceful gastric propulsions, converts food into chyme. The chyme is then delivered in
metered doses to the small intestine where the majority of digestion and absorption occurs.
The physiological process that is central to the functioning of digestive system is absorption. All
other processes subserve it. Improper regulation of secretion and motility results in GI disorders.
• Neurohormonal regulation of motor and secretory functions
• To optimize digestion and absorption to take place
- Secretion is controlled to provide enzymes, fluids and electrolytes in the proper locations, at the
right times, and in the required quantities so as to digest foodstuffs
- Motility is regulated to move meal through the GI tract at rate optimal for digestion and
subsequent absorption
2. Principles of digestion and absorption
2.1. Structural considerations
- Most digestion and absorption take place in the small intestine
- Macroscopic surface area is 2.5 m2
- Structural modifications increase overall area to 400 m2
Thus, there are several mechanisms involved in order to enhance the absorptive areas of our small
intestine:
• Folding of intestinal surface
• Extending from its surface is “finger-like projections” called, villi
• The apical surface of each villus is further covered with microvilli or brush border (Fig. 7-1).
_______
Cells
Crypt cells
Fig. 7-1. Diagram showing intestinal villi and crypt. Cell types and functions of individual cells are noted (Johnson’s Essential
Medical Physiology, 1998).
57
2.2. Digestion: Overview

Digestion is the chemical breakdown of ingested food into absorbable forms using digestive
enzymes. There are two types of enzymes and digestion (Fig. 7-2).
• Luminal
- Take place in GI lumen by enzymes secreted from salivary glands, stomach & pancreas
• Membrane-bound
- Take place in brush border by enzymes bound to enterocytes of the villi
Fig. 7-2. Source of the principal luminal and membrane-bound digestive enzymes (Johnson’s GI Physiology, 2007).
2.3. Prevention of autodigestion
2.3.1. Activation of pancreatic proteases

The five major proteases secreted from the pancreas are synthesized as inactive precursors in the
acinar cells. Trysinogen is first converted to active trypsin by the brush border enzyme
enterokinase when it arrives in the duodenum (Fig. 7-2-1). Trypsin is autocatalytic and once
enterokinase initiates the process, most the remaining trypsinogen is activated by trypsin. Trypsin
then converts the other four proteases into active forms. This provides a protection for the
autodigestion of the pancreas. Clinically, premature activation of trysinogen before emptying
into the duodenum may lead to pancreatitis (Please see CC of Lecture 5). The pancreatic proteases
also digest each other, so these enzymes are rapidly inactivated within lumen. These secreted
proteins are digested and absorbed in the same manner as dietary protein, as discussed in the
following section (see Section 5).
Fig. 7-2-1. Means of activating the pancreatic proteases that are secreted as proenzymes. Trypsinogen is activated by
enterokinase. The resulting trypsin converts the other proenzymes plus additional trypsinogen (Johnson’s Essential Medical
Physiology, 2003).
58
2.3.2. Pepsinogen secretion
Another example for the prevention of autodigestion of GI system is demonstrated in the pepsin
secretion. Pepsin is secreted by chief cells in the form of an inactive precursor called pepsinogen.
The acidity in the stomach’s lumen alters the shape of pepsinogen, exposing its active site so that
this site can act on other pepsinogen molecules to break off a small chain of amino acid from their
ends. This cleavage converts pepsinogen to pepsin, the fully active form. The activation of pepsin is
an autocatalytic, positive feedback process that occurs in the gastric lumen, thus preventing damage
to the inner layer of the stomach (Fig. 7-2-2).
_____
Fig. 7-2-2. Conversion of pepsinogen to pepsin in the lumen of the stomach (Vander’s Human Physiology, 2011).
2.4. Absorption: Overview

Absorption is the movement of nutrients, water and electrolytes through the epithelial cell lining
into the blood or lymph.
The pathways taken by nutrients on their journey from the lumen of the intestine to the blood or
lymph are shown in Fig. 7-2-3. They actually consist of eight different barriers:
Absorptive pathways consist of eight barriers (the pathways 3 & 5 are the major ones):
1. An unstirred layer of fluid

2. A glycoprotein surface, the glycocalyx
3. The apical membrane of the enterocytes
4. The cytoplasm of the enterocyte
5. The basolateral cell membrane
6. The intercellular space
7. The basement membrane
8. The wall of capillary or lymph vessel.
The first two and the last three layers are normally crossed by simple diffusion; specific carrier-
mediated transport processes exist in the apical and basolateral membranes for most electrolytes
and nutrients. Blood is supplied to each villus by one or more central arterioles, which break up
into capillaries that form a network beneath the bases of the absorbing cells. Eventually, this blood
drains into the portal vein. Each villus contains a central lymphatic vessel called a lacteal. The
products of fat digestion enter the lacteals and, eventually, the blood stream via the thoracic duct.
59
Fig. 7-2-3. The pathway traversed by absorbed solutes. Beginning in the lumen, barriers consist of an unstirred layer of fluid, the
glycocalyx, the apical cell membrane, the cytoplasm of the enterocytes, the basolateral cell membrane, the intercellular space, the
basement membrane, and finally, the wall of the capillary or lymphatic vessel (Johnson’s GI Physiology, 2007).
3. Basic transport mechanisms of cell membrane
Five basic transport routes are employed by intestinal enterocytes for the absorption of nutrients
and ions as well as water. They are:
• Simple diffusion
• Facilitated diffusion
• Active transport
- Primary (energy derived directly from ATP)
- Secondary (energy derived secondarily in the form of ionic concentration difference)
• Pinocytosis
• Paracellular transport through tight junctions
4. Assimilation of carbohydrates
Three major classes of carbohydrates:
• Monosaccharides
- glucose, galactose, fructose
• Oligosaccharides
- sucrose, lactose, maltose
• Polysaccharides
- starch, cellulose, glycogen
4.1. Digestion of carbohydrates

- Make up ~50% of typical American diet
• Starch (50%) • Sucrose (30%)

• Lactose (6%) • Maltose (2%)
• Glucose, fructose, cellulose
60
Starch contains two types of glucose polymer, amylose and amylopectin. The former consists of
long, unbranched chains of D-glucose connected by (a1®4) linkages (Fig. 7-3a). Amylopectin
consists of highly branched glucose connected not only by (a1®4) linkages but also by branched
points (a1®6) linkages (Fig. 7-3 b & c).
Fig. 7-3. Amylose and amylopectin, polysaccharides of starch. (a). Amylose, a linear polymer of D-glucose units in (a1®4)
linkage. (b). Amylopectin, a branched polymer. (c). Structure of an (a1®6) branch point
4.2. Absorption of carbohydrates
Carbohydrate digestion produces three absorbable monosaccharides:
• Glucose
- By secondary active transport (Na+-dependent, SGLT1)
• Galactose
- By secondary active transport (identical to that of glucose)
• Fructose
- By facilitated diffusion (separate transporter, GLUT5)
4.3. Mechanism of glucose/galactose carrier system
Transport of glucose and galactose involves the same carrier system. The absorption involves a
secondary active transport from the intestinal lumen using a Na+-dependent hexose co-transporter
(SGLT1) with specificity for both glucose and galactose. The system is energized by a primary
active pump, Na+/K+-ATPase, located in the basolateral membrane that maintains sodium gradient
favoring the entry of two Na+ into the cell, with the concomitant co-transport of substrate (S). Both
Na+ and glucose must be present in the intestinal lumen for active transport of SGLT1 (Fig. 7-4).
Water is passively transported by osmosis via paracellular route. The result of SGLT1 is net water
and electrolyte absorption along with glucose/galactose. Fructose is absorbed by a separate hexose
transporter (GLUT5). The exit of these simple sugars across the basolateral membrane to the blood
is accomplished by either the facilitative GLUT2 transporter or by simple diffusion.
61
Na+/K+-ATPase
SGLT1 for Glucose
GLUT2
GLUT5 for Fructose
Fig. 7-4. Schematic diagram showing the sodium-dependent carrier system for glucose-galactose absorption by the intestinal cell
(Johnson’s GI Physiology, 2007).
4.4. Absorption of carbohydrate

Luminal digestion by salivary and pancreatic a-amylase, which only attack the interior a-1,4-bonds
of starch, yields maltose, maltotriose and a-limit dextrins. The latter are oligosaccharides of
glucose, formed because the a-1,6-bonds and the a-1,4-bonds near the branched points are resistant
to amylase (Fig. 7-5). Instead, they are exhaustively digested to absorbable forms of sugars by the
membrane-bound enzymes including a-dextrinase and a number of disaccharidases (sucrase,
lactase, isomaltase and so on). There are generally overlapped specificities of each membrane-
bound oligosaccharidase, as demonstrated by the circled numbers which denote the approximate
percentage of substrate hydrolyzed by a particular brush border enzyme.
Disaccharides from
diet
(maltase)
(a -1,2 link)
(a -dextrinase)
(a -1,1-linkage of 2 glucose)
(b-1,4
link)
Fig. 7-5. Summary of carbohydrate assimilation (Johnson’s GI Physiology, 2007).
62
It is noted that, for lactose digestion, there is only one enzyme called lactase specific for its
degradation into glucose and galactose. For this reason, lactase deficiency is the most frequently
observed congenital disaccharidase deficiency in newborn, or in adults, acquired in the late life
(lactose intolerance).
*For additional information on lactose intolerance, please see CC of this Lecture.
Diarrhea caused by the poor assimilation of dietary carbohydrates is most commonly due to
deficiencies of carbohydrate-splitting enzymes in the intestinal brush border (see Section 4.2. of
Lecture 11).
5. Assimilation of proteins
Dietary protein intake varies greatly among individuals of like background and among groups with
different geographical, cultural and economic foundations. Adult humans require 0.5 to 0.7 g of
protein per kg of body weight per day to maintain nitrogen balance. Young children may require 4
g per kg per day.
5.1. Basic structure of protein
- Dietary proteins are formed of long chains of amino acids (AA)

- AA are bound by peptide linkages/bonds to form dipeptide, oligopeptide or polypeptide
- 20 amino acids are present in the forms of L-isoforms in nature
(D-forms are not absorbable, i.e. absorption of AA is stereospecific)
• Neutral: Phe, Tyr, Gly

• Basic: Lys, Arg
• Acidic: Glu, Asp
• Imino: Proline plus b and g amino acids
5.2. Digestion of proteins

The two general classes of pancreatic proteases are endopeptides and exopeptidases. The basis of
classification and the particular characteristics of specific enzymes beginning to each class are
given in Table 7-1.
5.2.1. Proteins for digestion
• Ingested (dietary) protein

• Enzymes and mucus from GI secretion
5.2.2. Two types of peptidase
• Endopeptidases
- Luminal enzymes from stomach and pancreas
• Exopeptidases
- Carboxypeptidase from pancreas
- Aminopeptidase from membrane-bound enterocyte
(it is an exopeptidase but NOT a luminal enzyme)
63
Table 7-1. Major luminal enzymes

Enzyme Primary action
Endopeptidases Hydrolyze(s) interior peptide bonds containing
Pepsin Aromatic amino acids
Trypsin Basic amino acids; produces peptides with C-terminal
basic amino acids
Chymotrypsin Aromatic amino acids, leucine, methionine & glutamine;
produces peptides with these amino acids at C-terminus
Elastase Neutral aliphatic amino acids; produces peptides with these at C-
terminus
Exopeptidases Hydrolyze(s) external peptide bonds containing
Carboxypeptidase A Aromatic and neutral aliphatic amino acids at the C-terminus
Caroboxypeptidase B Basic amino acids at the C-terminus
5.3. Absorption of proteins
Protein digestion produces three absorbable forms:

• Free amino acids
- By carrier-mediated transport system requiring Na+ (Table 7-2)
• Dipeptides
- By a separate carrier-mediated transport
• Tripeptides
- By the same as dipeptides
Note: Intact protein cannot be absorbed in significant amounts EXCEPT in infants, where ileal
absorption of immunoglobulins in the mother milk is immunologically important.
Table 7-2. Free amino acid carrier systems in brush border membranes. Those in bold face are essential
AA that cannot be synthesized by humans and thus must be obtained from the diet.
Carrier Amino acids transported
Neutral (NBB) Aromatic: Phe, Tyr, Trp
Aliphatic: Gly, Ala, Val, Leu, Ile; Hydroxyl containing: Ser,
Thr;
Suphur containing: Cys, Met
Basic (Cationic) Lys, Arg, His
Acidic (Anionic) Glu, Gln, Asp, Asn
Imino Pro
Free AA can be absorbed across the brush border by different Na+-dependent transport systems
whereas they exit the basolateral membrane by Na+-dependent and independent transporters.
Figure 7-6 summarizes the digestion and absorption of protein. Defects in brush-border membrane
(BBM) or baso-lateral membrane (BLM) of enterocytes cause malabsorption of amino acids.
Hartnup disease and cystinuria are hereditary disorders of amino acid transport across the
BBM. These autosomal recessive disorders are associated with both small intestine and renal tubule
abnormalities; in the absorption of neurtal amino acids in the case of Hartnup disease and basic
amino acids in the case of cystinuria. Because neither of these diseases involves the oligopeptide
cotransporter, the absorption of small peptides containing either neutral or basic amino acids
is normal in both diseases.
*For defects of amino acid absorption, please see Tutorial 3 and CC of this Lecture.
64
Fig. 7-6. Summary of protein assimilation. Approximately one-third of the total amino acid is absorbed in free form after luminal
digestion. The remaining is absorbed as free acid or dipeptide or tripeptides following membrane bound digestion
(Johnson’s GI Physiology, 2007).
SUMMARY
• The digestive system is designed to break down complex nutrients sequentially into smaller and
smaller components (digestion) until they are reduced to a molecular size that can be transported
from the intestinal lumen to the body (absorption).
• All physiologically significant absorption of nutrients occurs in the small intestine, the mucosal
surface of which is greatly increased providing a large area for uptake.
• An outstanding property of the enterocyte membrane is its capacity to control the flux of solutes
and fluid between lumen and blood. This involves several mechanisms. Pinocytosis occurs at the
base of microvilli and may be a major mechanism in the uptake of protein. Other uptake protein
processes include passive diffusion, facilitated diffusion, and active transport.
• Besides defects in carbohydrate assimilation caused by the congenital or acquired enzyme
deficiencies, assimilation of dietary sugars may be impaired by diseases of the GI tract. Celiac
disease, certain bacterial infections, and some protozoan and helminth infections are associated
with inflammation and structural derangements in the small bowel mucosa (Further discussion is in
the lecture 10).
• Pancreatic insufficiency caused by various diseases, including cystic fibrosis and hereditary
pancreatitis, may lead to poor digestion of protein. Intestinal malabsorption of AA occurs in
various hereditary diseases such as Hartnup disease in which the active transport of several neutral
AA is deficient in both the renal and small intestine.
65
1. Clinical Note
Two carbohydrate malabsorption syndromes clinically encountered are Acquired lactase

deficiency or lactose intolerance (see Case Study below) and Congenital glucose-galactose
malabsorption. Glucose-galactose malabsorption is a very rare autosomal recessive disorder
resulting from a missense mutation in SGLT1. Ingestion of milk, glucose or galactose leads to
watery diarrhea shortly after birth. Fructose is, however, well tolerated to these infants because
fructose absorption has a separate glucose transporter (GLUT5), via a facilitated diffusion, which is
different from SGLT1. Interestingly, a milder mutation in SGLT1 results in reducing
transport activity of this protein partially as clinically implicated in IBS (see CC in Lecture 1,
p.10).
2. Clinical Focus
LYSINURIC PROTEIN INTOLERANCE (LPI)

• This is a rare autosomal recessive disorder of amino acid (AA) transport across the baso-lateral
memebrane (BLM). There is evidence of impaired cationic amino acids (such as lysine) transport
and symptoms of malnutrition. In Hartnup disease or cystinuria, the enterocytes can absorb AA
normally if it is presented as small peptides or high-protein diet. In LPI, however, the enterocytes
CANNOT absorb the amino acid regardless of whether the amino acid is free or in the form of
oligopeptides.
• The common symptom of patients with LPI is malnutrition and mild diarrhea. Because lysine
cannot be absorbed into the blood via the BLM of enterocytes, lysine infusion is recommended for
this clinical condition.
• Compare the defects of luminal AA transport or absorptive disorders at the level of the BLM (e.g.
LPI) with BBM (e.g. Hartnup’s disease and Cystinuria; see also Tutorial 3).
3. Case Study
A 50-year-old Asian man presents to a gastroenterologist with abdominal cramps and distension as
well as excessive gas and watery diarrhea. He denies vomiting, fever, or chills and any travel
recently. He is otherwise healthy. He notes that eating ice cream and drinking milk tend to provoke
the symptoms. The gastroenterologist administers 50 g of lactose orally to the patient and measures
an increase in his expired hydrogen gas (Lactose-H2 breath test).
Resolution: Lactose Intolerance

• The ability to digest milk sugar, or lactose, depends on the presence of a brush border enzyme
called lactase. This enzyme is high during childhood, but fails and becomes inactive to some
degree in most adults. People of Asian or African are more lactase deficient than Caucasians. A
deficiency of lactase can result in lactose intolerance, a condition in which undigested lactose
in intestine causes diarrhea, gas, cramps, and other unpleasant symptoms.
• A positive result of lactose breath test indicates lactose intolerance. Patient with lactase
deficiency is not able to digest lactose, which is then metabolized by gut bacteria to hydrogen gas
that is absorbed and appears in the breath.
• Avoidance of lactose-containing foods is recommended to relieve the symptoms. Alternatively,
bacteria-laden lactase tablets can be taken to replace the deficient brush-border enzyme.
66
LECTURE 8 & 9: Digestion and Absorption II & III
Learning Objectives
• Compare the basic principle of digestion and absorption of fat with carbohydrate and protein
• Understand the basic principles of absorption of fat-soluble and water-soluble vitamins
• Understand the basic principles of absorption of electrolytes and water
• Discuss their dysfunctions and their clinical relevance
1. Fat
The daily dietary intake of fat varies from below 25g, or less than 12% of caloric intake (among
rice-eating Oriental cultures), to as much as 140 to 160 g, or 40% of the caloric intake (among
meat-eating Western cultures).
Because fat is insoluble in water, the assimilation of dietary fat by the body is a complicated
process. Compared with the digestion of carbohydrates and proteins, numerous steps are involved
before dietary fat reaches the bloodstream for distribution. A problem in any one of these steps can
result in an abnormality in lipid assimilation. In addition, fats tend to remain in the stomach longer
than other nutrients. Fat within the duodenal lumen inhibits gastric emptying, so this ensures that
lipids do not enter the duodenum faster than they can be processed; this makes one feel “fuller” for
a longer time than does other meal (see “Regulation of gastric emptying” in Lecture 3).
1.1. Three sources of lipases

Several important enzymes including the pancreatic lipases are involved (Fig. 8&9-1).
• Food-bearing lipase, e.g. milk lipase
• Salivary lingual lipase
• Pancreatic lipases
Lipase-colipase (a specific enzyme for triglyceride)
Phospholipase A2 (an enzyme for phospholipids e.g. lecithin)
Cholesterol esterase (a non-specific lipase)
Fig. 8 & 9-1. Three major classes of dietary fat and their digestion products. The primary enzymes involved in digestion are also
illustrated (Johnson’s Essential Medical Physiology, 1998).
67
1.2. Digestion and absorption of fat

Assimilation of fat involves 2 processes: emulsification of fat and formation of micelles.
Emulsification of fat requires that (1) Large fat globule (about 1 mm in diameter) is subject to the
churning action of the stomach into smaller droplets or emulsion (3 µm); (2) An emulsifying
agent (bile acids and phospholipids) acts to prevent the emulsion droplets from re-aggregating
back into large droplets (Fig. 8&9-2). Emulsification of fat provides large surface area of fat,
which can be acted upon by pancreatic lipase such that digestion of fat can be accomplished. Co-
lipase can form a complex with lipase that is able to bind to bile salts and thus prevent the
inactivation of lipase by bile salts.
Although digestion is speeded up by emulsification, absorption of the water-insoluble products

would still be very slow if it were not for a second action of bile, the formation of micelles.
Micelles are similar in structure to emulsion droplets but are much smaller (4 to 7 nm); they
consist of bile salts/fat digestion products together with fat-soluble vitamins. The latter (BUT not
bile salts) can enter into the enterocytes by simple diffusion (Fig. 8&9-3).
Note: It is noted that bile salt components of micelles, unlike fats, are not absorbed in the upper
small intestine, but are used to form more micelles before finally being absorbed in terminal ileum.
Micelles therefore have a solubilization and shuttle function.
~ 3 µm
~ 1 mm
Water soluble
aggregates
~ 3 µm
~ 7 nm
Fig. 8 & 9-2. Emulsification of fat by bile salts Fig. 8 & 9-3. Digestion of fat and formation of micelles by
bile
and phospholipids. salts and phospholipids (Vander’s Human Physiology, 2011).
1.3. Intracellular processing of fat digestion products

Within the enterocytes, the products of lipolysis are resynthesized into triglycerides in smooth
endoplasmic reticulum (ER), which are taken up in the form of chylomicron by the lymph vessels
in the villi. There are two different pathways of resynthesis: the major one, monoglyceride
acylation pathway and the minor one, phosphatidic acid pathway (Fig 8&9-4). The chylomicron
leaves the cells by exocytosis, enter the lymph vessels of the villi, and eventually pass into the
venous circulation.
68
Fig. 8 & 9-4. Summary of digestion and absorption of triglycerides, re-synthesis and chylomicrons formation. Monoglycerides
and long-chain fatty acids enter the cells after first being incorporated into micelles. Glycerol and short-chain and medium-chain
acids, because of their solubility in the aqueous unstirred layer, enter without micelle solubilization (Johnson’s GI Physiology,
2007).
Note: In clinical setting, malabsorption of lipids occurs more frequently than malabsorption of
proteins and carbohydrates.
It can be caused by bile deficiency, pancreatic insufficiency or intestinal mucosal atrophy. For
the first two to occur, the levels of bile acids and lipolytic enzymes must be severely reduced. In
tropical sprue and gluten enteropathy, the intestinal epithelium is flattened and the density of the
microvilli is decreased (see Section 4.2 of Lecture 11).
*Please see additional information on CC of this Lecture.
2. Absorption of vitamins
Most water-soluble vitamins are absorbed by simple or facilitated diffusion in upper small
intestine. Vitamin B12 is, however, absorbed by a specific transport mechanism in distal ileum,
which is dependent on the secretion of intrinsic factor from gastric parietal cells. Fat-soluble
vitamins are absorbed by simple diffusioin - a process which requires their solubilization within
micelles and therefore dependent on adequate secretion of bile.
- Organic compounds required in small quantity

- Act as co-factors or co-enzymes for metabolic reactions
- Not synthesized and must be obtained from diet
- Absorption follows the basic principle as those for nutrients
- Based on whether they are fat-soluble or water-soluble
- Simple diffusion and carrier mediated transport
69
Table 8 & 9-1. Fat-soluble and water-soluble vitamins

Vitamin Water-soluble Fat-soluble
A (Retinol) +
B1(Thiamine) +
B2 (Riboflavin) +
B6 (Pyridoxine) +
B12 (Cobalamin) +
C (Ascorbic acid) +
D (Calciferol) +
E (a-, b-, g- Tocopherol) +
K (Phylloquinones, menaquinones) +
H Biotin +
M Folic (Pteroyglutamic) acid +
Niacin (Nicotinic acid) +
Pantothenic acid +
Note: Vitamin K is a fat-soluble vitamin and its absorption depends on normal fat absorption.
There are two primary sources: (1) Phylloquinones obtained from the diet of leafy green
vegetables and (2) Menaquinones produced by intestinal bacteria. Vitamin K is essential for the
carboxylation of certain glutamate residue in coagulation factors (Factors II, VII, IX and X). Thus,
deficiency of vitamin K can lead to a serious bleeding disorder: its common causes include liver
problem thus resulting in inadequate secretion of bile acids; pancreas problem thus resulting in
inadequate secretion of pancreatic lipase; intestinal microflora impairment (e.g. use of antibiotics
in hospitalized patients); reduced absorptive villi (e.g. celiac disease). All of the above causes can
lead to fat malabsorption concomitant with vitamin K deficiency. See also Clinical Focus
“Steatorrhea” of this Lecture.
2.1. Absorption of vitamin B12 or cobalamin (Fig. 8 & 9-5)
- Vitamin B12 bound to R proteins in stomach

- R proteins degraded by proteases and bound to IF in intestine
- IF-B12 complex bound to its receptor (cubilin) and absorbed into the ileum
Fig. 8 & 9-5. Absorption of vitamin B12 or cobalamin (Cbl).
70
2.2. Malabsorption of B12
- Pancreatic insufficiency
- Deficiency in IF secretion by parietal cells (e.g. autoimmune type)
- Malabsorption disorder for the IF-B12 complex in distal ileum
Note: Whether B12 malabsorption is due to a reduced IF secretion or IF-B12 absorption can be
clinically assessed (see CC “Schilling Test” of this Lecture).
3. Electrolyte and water transport
- In addition to digesting and absorbing nutrients, GI tract is also very important in absorbing ions
and water
- Failure to do so would lead to dehydration and electrolyte imbalance
- After passing through the small intestine & colon, 100 ml water left, relatively few in Na+ and Cl-
, BUT rich in K+ and HCO3-
About 85% of the 9 L of water and 35g of NaCl presented to the GI tract daily are absorbed by the
small intestine. All but 100-200 ml of the remaining fluid is reabsorbed by the colon (Fig. 8&9-6).
Water and electrolytes may cross the enterocyte membrane of the GI tract through transcellular and
paracellular routes (Fig. 8&9-7). The transcellular route involves movements across the apical
and basolateral membranes in series. The paracellular route involves movements through the
tight junctions, and the underlying intracellular space.
The permeability of these two routes depends on the locations of the GI tract. In the duodenum, its
epithelial cells are very leaky and thus paracellular route is dominant; in the ileum, its epithelial
cells are much tighter and thus transcellular route is the major route.
Fig. 8 & 9-6. Volumes of fluid entering and absorbed Fig. 8 & 9-7. Transcellular and paracellular routes by
enterocytes
daily by the intestine, and excreted in the feces. (Johnson’s Essential Medical Physiology,
1998).
71
Table 8 & 9-2. Transport of Na+, Cl-, K+ and HCO3- in GI tract
Regions Na+ Cl- K+ HCO3-

Jejunum Active Absorbed Passive Absorbed
on H2O
Ileum Active Absorbed Passive Secreted

in in
exchange exchange
Colon Active for Net for
HCO3- secretion Cl-
3.1. Mechanisms for the absorption of sodium ions by intestinal cells
Four basic mechanisms have been identified that are responsible for the movements of Na+ ions
from the mucosal solution across the apical membranes of enterocytes (Fig. 8-8).
Fig. 8 & 9-8. Four different mechanisms for the absorption of Na+ by intestinal cells.
SUMMARY
• Water-insoluble monoglycerides and fatty acids, the end products of pancreatic lipase of
triglyceride, interact with bile salts to form water-soluble aggregates called micelles. Fat digestion
products diffuse passively from micelles into the enterocyte where they are resynthesized to
triglycerides and passed on to the lymph as chylomicrons.
• Four mechanisms account for Na+ absorption: (1). Passive diffusion, (2). Counter-transport with
H+, (3). Cotransport with organic solutes (sugars & amino acids), and (4). Co-transport with Cl- .
• The absorption of water occurs by diffusion down an osmotic gradient created by the absorption
of Na+, Cl- and other electrolytes and nutrients.
72
1. Clinical Focus
STEATORRHEA
• The clinical condition is characterized by greater than normal amounts of fat in the feces with
frothy, foul-smelling and floating fecal matter.
• It is due to inadequate luminal digestion and absorption of triglycerides in pancreatic exocrine
insufficiency. Impaired digestion may be due to decreased pancreatic lipase activity including such
conditions as pancreatitis, cystic fibrosis, and other pancreatic diseases. Impaired absorption
may be due to malabsorption such as in celiac disease. With deficiency of pancreatic lipase, two-
thirds of dietary fat is not absorbed and appears in the stool as undigested triglyceride.
• Increased acidity of the duodenal contents resulting from gastric acid hypersecretion
(Gastrinoma) or inadequate bicarbonate secretion may lower the pH significantly below the
optimum for pancreatic lipase or denature the enzyme.
ABETALIPOPROTEINEMIA (See Case Study 2 below)
• In certain disorder, lipids are malabsorbed and chylomicrons do not appear in intestinal lymph.
In such case, intestinal epithelial cells become engorged with lipid, and few chylomicrons are
exported.
• In abetalipoproteinemia, apo-B is missing from serum lipoproteins. Failure to synthesize
apoprotein B prevents chylomicron formation, thus leading to a buildup of fat within the enterocyte.
CELIAC DISEASE (See Case Study 2 of Lecture 11)
• Celiac disease (celiac sprue) or gluten-sensitive enteropathy is a condition characterized by

inflammatory reaction of the intestinal villi that result from an intolerance to dietary gluten
(gliadin, an active gradient in wheat barley, rye, oat, and cereal).
• Immunologically mediated inflammation (GALT) leads to loss of villi and thus malabsorption of
nutrients ensues. Sign and symptoms include iron-deficiency induced anemia (Why?), diarrhea,
weight loss and steorrhea.
• Standard treatments: (1). Withdrawal of diets containing gluten and (2). Glucocorticoid therapy
(because of its anti-inflammatory and immunosuppressive effects). For clinical manifestations, see
Case Study 2 in Lecture 11, p.87.
PANCREATIC CANCER
• Pancreatic ductal adenocarcinonma (PDA) accounts for 90% of all pancreatic cancers, which is a
very aggressive malignant tumor that usually occurs within the head of the pancreas. Cf Pancreatic
endocrine tumor (insulinoma, glucagonoma, somatostatinonma, gastrinoma & VIPoma).
• The cause of PDA is mainly associated with mutations of specific proto-oncogenes, tumor-
suppressor genes and transcription factors.
• Poor prognosis; clinical findings include midgastric pain, weight loss, clay-colored stools, glucose
intolerance, and obstructive jaundice. Note: The main cause of obstructive jaundice is gallstone-
induced (see Case Study of Lecture 6. p.56), but not pancreatic cancer-induced.
• Treatments include surgical resection, chemotherapy and radiotherapy.
73
SCHILLING TEST
• A test is used clinically to assess B12 absorption either in patients with PA or those with ileal
disease/resection.
• Patients with PA have diminished IF secretion and those with ileal disease/resection have reduced
absorption of IF-B12 complex.
• A tracer dose of radioactive B12 is given orally, and 1-2 hours later a large dose of unlabeled B12
is given intramuscularly to saturate plasma binding sites so that most of the absorbed B12 is excreted
in the urine.
• If the urinary excretion of radioactivity is low (<8%), a second-stage test is done in which IF is
given orally along with the radioactive B12.
• PA patients have reduced radioactive B12 absorption that normalizes when given IF orally; those
with ileal disease/resection have, however, diminished absorption in both parts of the Schilling test.
2. Case Study
2.1. Case study

A 10 year-old girl presents with chronic diarrhea described as 4-5 large bulky stools a day and
failure to grow. On a 100g fat diet she excretes 40g in her stool predominantly in the form of
triglycerides. Analysis of her duodenal fluid after stimulation of the pancreas by an injection of
secretin shows a very low concentration of bicarbonate and pancreatic lipase. She is started on oral
porcine pancreatic enzyme extracts (Creon*) and notes a decrease in bowel movements to 2-3 per
day and improvement in her weight and height.
*CreonÒ is a capsule of pancrelipase which is a combination of porcine-derived lipases, proteases,
and amylases indicated for the treatment of exocrine pancreatic insufficiency due to CF, CP,
pancreatectomy, or other conditions.
Q1. What is the cause of her fat malabsorption?

Hint: CFTR (CFTR gene mutation) or CP (trypsinogen gene mutation) induced pancreatic
insufficiency.
Q2. Why this patient can still absorb some dietary triglycerides?
Q3. What limits the activity of pancreatic enzymes administered orally to this patient?
Q4. How might you improve activity of these enzymes?
Q5. What clinical assessments could be used for the diagnosis of the disease? (see CC, L5, p.45).
2.2. Case study

A one-year old boy presents with diarrhea, poor growth and multiple neurologic problems. A
peripheral blood smear shows acanthocytes (abnormal red blood cells with spur-like projections).
He is found to have increased fat in his stool (steatorrhea), very low blood levels of apoprotein B,
cholesterol, triglycerides, and vitamin E. Intestinal biopsy shows normal villus architecture. Fat-
laden epithelial cells are observed by Sudan staining of the biopsy.
Q1. What is the diagnosis of this boy?

Q2. What is the cause of his fat malabsorption?
Q3. What form of fat is wasted in his stool?
Q4. How to explain the clinical observations of neurologic problems in this patient?
Q5. Why abnormal red blood cells (acanthocytes) are found in this patient?
Q6. What treatment would you recommend for the patient?
74
LECTURE 10: Gastrointestinal Disorder I
Learning objectives
• Appreciate how GI disorders are caused by dysfunctions of motility and secretion
• Describe the basic principles of motility dysfunction exemplified by achalasia
• Describe basic principles of secretory dysfunction exemplified by gastrinoma & ulcers
• Apply the basic knowledge of GI physiology to abnormal physiology
GI disorders can be described in term of dysfunctions in motility and secretion. As GI motility is a

complex result of smooth muscle contraction under neural and hormonal regulation, abnormal
motility of GI tract can occur through damage to GI smooth muscle or to the neural and
hormonal mechanisms by which it is controlled, or to both.
1. Achalasia
The lower esophageal sphincter (LES) has a very important function in allowing food to enter the
stomach and preventing the reflux of gastric contents back into the esophagus. At least two serious
diseases - reflux esophagitis and achalasia (discussed below) can be attributed to dysfunction of
the LES. For the regulation of esophageal motility, please refer to Section 4 of Lecture 3
“Esophageal motility”, p.25.
- The best-known motility disorder of esophagus
- Insufficient peristaltic waves and increase in LES pressure
- Due to the loss of relaxing factor-secreting ENS neurons
- Uncoordinated peristalsis and impaired swallowing
• Diagnosis
- Barium radiology/endoscopy or manometric studies (Fig. 10-1).
• Treatment
- Using pneumatic device (forceful balloon dilatation), anti-spasmotic drugs (calcium blockers and
nitrates) or surgical options (myotomy). Please see Tutorial 1 for discussion.
Fig. 10-1. Pressures in the pharynx, esophagus, and esophageal sphincters during swallowing (Berne & Levy’s Physiology, 2004).
75
Both pneumatic dilatation and surgery work by forcefully disrupting LES fibers and by markedly
reducing LES pressure, respectively. The former involves forceful balloon dilatation of LES while
the latter cuts circular muscle of LES. Pneumatic dilatation is not a permanent solution and some
patients require repeated dilatations over time. Gastroesophageal reflux disease (GERD) is the
complication of the treatments (see Point 2 of Summary, p.86).
1.1. Factors that influence the LES motility
LES pressure is affected by many endogenous endocrine and neurocrine factors, as well as by
several food substances, which may be either excitatory or inhibitory (Table 10-1). Among
them, NO and VIP are the primary inhibitory factors that markedly induce LES relaxation.
Normally, the LES is richly innervated by VIP- and NO- secreting myenteric neurons in ENS.
Neuropathy or degeneration of myenteric neurons causes loss of inhibitory tone, thus leading to a
functional obstruction of the esophagus, as manifested by achalasia (more discussion in Tutorial
1).
Table 10-1. Factors that are believed to have physiological role in the regulation of LES pressure
Regulators Increase Decrease

Hormones Gastrin CCK
Secretin
Neurocrines ACh VIP
(Vagal & ENS) SP NO
Foods & others Protein Chocolate

Antacids Ethanol
Smoking
2. Peptic ulcer disease (PUD)
A peptic ulcer can be caused by either of two ways:

• Excess secretion of acid and pepsin
• Diminished ability of the gastric mucosal protection system
- Mucus
- Bicarbonate
- Replacement of damaged cells (restitution)
- Acid
- Prostaglandins (a cytoprotective factor)
*See Discussion of “Gastric mucosal barrier” and “Gastric acid secretion” of Lecture 4
2.1. Prostaglandins
Prostaglandins are derived from arachidonic acids in the cell membrane via the enzymatic activity
of cyclooxygenase (COX) in multiple sites of GI system. These 20-carbon-long fatty acids act as a
cytoprotective factor via a paracrine/autocrine pathway. Prostaglandins can inhibit gastric
secretions and influence intestinal motility and fluid absorption.
- secreted by mucus, chief and parietal cells

- antisecretory effect
- mucus and HCO3- stimulation
76
- increasing mucosal blood flow

- reducing mucosal H+ ion back-diffusion
- enhancing cell turnover
The causes and common site for PUD are shown in Fig. 9-2.
Causes:
1. High acid/pepsin levels
2. Irritation (e.g. Drug-induced)
3. Poor blood supply
4. Impaired mucus & HCO3- secretion
5. Infection (H. pylori) Lower end of
esophagus
close to LES
Lesser
curvature of
antral end
First few cm of duodenum

close to pylorus
Fig. 10-2. The causes and most frequent site for peptic ulceration
2.2. Physiological roles of gastrin

Gastrin is a GI peptide hormone produced by G-cells in gastric antrum and to a lesser extent in
duodenum. Excessive secretion may be produced in gastrinoma.
- stimulate gastric acid secretion by parietal cells

- stimulate growth of gastric gland mucosa, especially the trophic action on parietal cell
- increase gastric motility
- increase intestinal electrolyte & water secretion, especially in high level of serum gastrin
- negative feedback mechanism of gastrin and acid
2.3. Negative feedback of gastrin and acid

Because of the feedback mechanism whereby antral acidification inhibits gastrin release, the
general statement can be made that serum gastrin levels are related inversely to acid secretion
capacity. Patients with gastric ulcer and carcinoma usually have higher than normal serum gastrin
levels. Serum gastrin levels in pernicious anemia actually may approach those seen in gastrinoma.
Obviously, gastrinoma patients are an exception to this rule because their hypergastrinemia is
derived not from the antrum but from a tumour not subject to inhibition by gastric acid
(Table10-2).
77
Table 10-2. Comparison of acid output and serum gastrin values from human stomach in normal and disorder
conditions
Condition Basal acid output Serum gastrin

(mmole/hr) (pg/ml)
Normal 3 100
Pernicious anemia 0 Very high
Gastric ulcer 1.5* Higher than normal
Duodenal ulcer 6* Lower than normal
G cell hyperplasia 15 Abnormally high
Gastrinoma 20 Abnormally high
(Zollinger-Ellison syndrome) > 1000
*Reason for these observations may be due to H. pylori infection (see Section 1, Lecture 11).
3. Gastrinoma (Zollinger-Ellison syndrome)
Pancreatic endocrine tumour (PET) is the endocrine tumour arising from cells in pancreatic islets.
Based on which endocrine hormone is abnormally produced, PET can be named as gastrinoma,
insulinoma and glucagonoma
- In peptic ulcer, usually higher than normal gastrin levels

- Pancreas or duodenal tumors producing exaggerated gastrin
- Gastrin release is not subject to acid feedback inhibition
- Resulting in constant release of gastric acid
- This hypergastrinemia results in hypersecretion of acid
3.1. Two synergistic effects of hypergastrinemia
Hypergastrinemia that results from gastrinoma free of regulatory restraints:

• Over-stimulation of gastric parietal cells to secrete acid
• Increased mass of parietal cells susceptible to over-stimulation
Note: Hypersecretion of acid and gastrin lead to severe duodenal ulcer and persistent diarrhea
Table 10-3. Gastrin provocative test for distinguishing hypergastrinemia of gastric origin (G cell hyperplasia) from
gastrinoma of pancreatic origin
Condition Secretin test Meal test

Normal minor +
Gastrinoma + -
Antral G cell hyperplasia - +
“+” shows positive test (gastrin increase >200 pg/ml); “-“ shows negative test (no significant
increase); “minor” shows little inhibitory effect of secretin on gastrin release
Note: Secretin strongly suppresses acid secretion while it has little effect on the gastrin release in a
normal subject (see Table 4-1, Section 6 of Lecture 4). However, secretin stimulates PET cells to
release gastrin from a patient with gastrinoma. The mechanism may involve direct activation of a
secretin receptor expressed on gastrinoma cells. This receptor has not been, however, found on
antral G cells.
78
4. Etiological factors for peptic ulcers
There are a number of factors that could be associated with PUD (Table 10-4). The use of non-
steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen may
cause PUD. These drugs are commonly used for treatment of joint inflammation. NSAID-induced
ulcer may be involved in the ability of these drugs to inhibit gastric prostaglandin synthesis via two
isoenzyme forms of cyclooxygenase (COX1 & COX2). While NSAID improves inflammation
via COX2 blockade, inhibition of COX1 causes gastric irritation.
Ethanol has long been known to cause damage to gastric mucosa, probably by virtue of its
lipophilic properties, thus disrupting the surface epithelium in the stomach. In addition, PUD is
frequently seen in patients suffering from various forms of shock such as endotoxic, hemorrhagic
and hypotensive ones. The potential mechanisms may be due to reduced blood flow in splanchnic
circulation and enhanced inflammatory mediators during shocks, trauma and burns. Recently, a
strong association between PUD and the bacteria, called Helicobacter pylori has been established;
the potential mechanism(s) by which H. pylori causes mucosal damage and PUD will be discussed
in Section 1 of Lecture 11.
Table 10-4: Some harmful factors that could be associated with peptic ulceration
Factors Potential Mechanisms
Non-Steroidal Anti-Inflammatory Inhibition of prostaglandin synthesis via COX1 &
Drugs (NSAIDs); 20% of PUD COX2
Alcohol Vascular damage and direct cytotoxic effects
Smoking Unknown; possibly inhibits gastric prostaglandin
synthesis and increases acid secretion
Corticosteroids Inhibition of repair of pre-existing damage; interfere
with acute inflammatory responses
Methylxanthines Stimulation of acid secretion
Shock/trauma/burns Reduced blood flow and/or generation of harmful
mediators
Helicobacter pylori Direct and indirect mucosal damage
(80% of PUD)
Note: H. pylori and NSAID-induced ulcers are the most common causes of PUD. The latter can
be improved by newer COX2-selective drugs such as celecoxib and rofecoxib that inhibit
inflammation with fewer negative side effects on the health of the gastric mucosa.
79
LECTURE 11: Gastrointestinal Disorder II
Learning objectives
• Appreciate how GI disorders are caused by dysfunction of motility and secretion
• Describe the physiology of H. pylori and its pathogenesis of peptic ulceration
• Describe the basic principles causing different categories of diarrhea
• Apply the basic knowledge of GI physiology to abnormal physiology
1. Infection of Helicobacter pylori and its pathogenesis of ulceration
In recent years, a strong association between PUD and H. pylori (a gram-negative and non-
invasive bacterium) colonization of the stomach has become apparent. For example, H. pylori can
be detected in virtually 100% and 95% of GU and DU patients, respectively. It should be noted that
bacterial infection is NOT necessarily manifested with PUD, which is dependent on the
immunological response of individual host.
Two questions: (1) How does H. pylori survive in an extremely acidic environment?
(2) How does H. pylori cause mucosal damage? (Fig. 11-1)
Fig. 11-1. Schematic diagram showing possible mechanism by which H. pylori causes mucosal inflammation and damage.
Note: The reason why H. pylori infection causes duodenal ulcer in one person and gastric ulcer in
another is not well known. Strong evidence indicates that H. pylori infection of the gastric body
(acid-secreting area) results in gastric ulcer while antral infection leads to duodenal ulcer. In
the gastric body, infection causes mucosal damage and decreased acid secretion (gastric ulcer)
whereas in the antrum (hormone-secreting area), infection inhibits somatostatin release thus
increasing acid secretion (duodenal ulcer).
2. Methods of diagnosis for Helicobacter pylori

I. Invasive (Antral biopsy)
A. Rapid diagnosis
• Gram’s stain
• Urease test
B. Delayed diagnosis
• Histological study
• Bacterial culture
80
II. Non-invasive
A. Serological testing for antibody to H. pylori
B. Urea breath test
2.1. Urea Breath Test

A non-invasive test of high sensitivity and specificity for H. pylori. Carbon-14 uses radioactivitiy
while C-13 requires expensive mass spectrometery.
Carbon-13 method has advantage over carbon-14 because of being non-radioactivity

13
C/14C*-labelled urea
(in liquid/capsule)
¯
Ascorbic acid
(delay gastric emptying)
¯ 30 min
Collect samples and check isotope activity
i.e. 14CO2 /13CO2 in expired air
An advantage of urea breath test over serological test (both of which are non-invasive methods) is
that positive urea breath test indicates an active infection of H. pylori. On the other hand, a
serological test is based on the detection of antibodies to H. pylori. A positive test, however, does
NOT indicate whether infection is curently present.
3. Drugs used in the treatment of peptic ulcer disease

Since peptic ulcer occurs because of an imbalance between acid secretion and gastric mucosal
defense system, treatment of ulcer diesease could be targeted for either using acid-depressants or
agents that enhance mucosal defense system (Table 11-1).
Table 11-1. Some treatments for PUD and the mechanisms of action
Treatment Potential mechanism of action
Antacids Neutralization of gastric acid
e.g. Al(OH)2, Mg (OH)2
H2 receptor antagonists Inhibition of histamine-dependent acid
e.g. Cimetidine & ranitidine secretion
H+/K+-ATPase inhibitors Inhibition of proton pump
e.g. Omeprazole & lansoprazole
Muscarinic receptor antagonist Inhibition of Ach-stimulated acid secretion
e.g. Pirenzepine
Prostaglandin agonist Inhibition of acid secretion;
e.g. Misoprosol Direct cytoprotection
(mucus & HCO3- stimulation)
Sucralfate Stimulation of prostaglandin synthesis
Bismuth salts Eradication of H. pylori
Carbenoxolone Stimulation of prostaglandin synthesis
Antimicrobials Eradication of H. pylori
e.g. Amoxycillin & clarithromycin
Note: The most frequent and effective regimen “Triple Therapy” is the use of either proton inhibitor
(omeprazole) or H2 receptor antagonist PLUS two to three antibiotics (e.g. amoxycillin and clarithromycin)
for 2 weeks. The triple therapy not only heals the uclers but also prevents the recurrence of ulcers.
81
4. Diarrhea
Diarrhea is an imbalance between absorption and secretion of intestinal water and electrolyte
(Figure 11-2). It results when excess water and electrolyte are actively transported into the lumen
of the GI tract or, when water is retained in the lumen by osmotically active molecules. Another
major contributor of diarrhea is the over-stimulation of GI motility.
Fig. 11-2. Absorptive and secretory flows in determining the net fluid movements (Johnson’s Essential Medical
Physiology, 1998).
4.1. Factors that stimulate intestinal secretion

Generally speaking, diarrhea is both secretory and associated with hyper-motility of the intestine.
Not all neuroendocrine tumours produce secretagogues that activate a true secretory diarrhea; some
cause only mild diarrhea. Other endocrine causes of diarrhea are listed below (Table 11-2):
Table 11-2. Some neuroregulators that stimulate secretion.

Agent Mediator Disease Association
VIP cAMP Pancreatic cholera
Secretin cAMP Diabetic diarrhea
Gastrin Calcium Thyroid carcinoma/Gastrinoma
Histamine Unknown Gastrinoma
Adenosine cAMP Systemic mastocytosis
Calcitonin Unknown Carcinoid syndrome
Serotonin Calcium Neural tumours
Cholinergic M agonists Calcium Mesenteric ischemia
Note: Among these neuroendocrine, pancreatic cholera is a syndrome of profound watery diarrhea
caused by VIP-secreting tumour in the pancreas. VIP stimulates water and electrolyte secretion by
binding to specific receptors on intestinal epithelial cells, thus increasing cAMP (see CC of Lecture
2). Gastrinoma is the most common neuroendocrine tumour that not only causes severe peptic ulcer
but also persistent secretory diarrhea (see Section 3 of Lecture 9 and Tutorial 2).
82
4.2. Types of diarrhea
There are different mechanisms of actions that can cause diarrhea, which can be manifested
clinically by different diseases. They include (1) Stimulation of net fluid and electrolyte secretion;
(2) Nutrient malabsorption; (3) Mucosal destruction and increased permeability; (4) Increased
propulsive muscle contractions. For simple classification, the etiology of diarrhea may be
subdivided into 3 broad categories:
A. Malabsorptive diarrhea due to impaired absorption by the intestine e.g. infection,

inflammation
e.g. Celiac disease (celiac sprue), a gluten-sensitive enteropathy. Diarrhea is caused by damage to
the intestinal mucosa produced in susceptible people by eating foods that contain gluten.
Gluten (protein from grains such as wheat) ® Inflammation ® Loss of villi (see Case Study of
this Lecture)
B. Osmotic diarrhea due to the accumulation within the intestine of nonreabsorbable solutes
e.g. glucose malabsorption or lactase deficiency
Note: Mechanism for osmotic diarrhea can be explained using an example of lactase deficiency or
lactose intolerance.
Lactase deficiency
¯
Accumulation of lactose in bowel lumen
(Lactic acid production by bacteria)
¯
Increased luminal osmolality in lumen
¯
Fluid accumulation in lumen
¯ Luminal distension
¯ ¯
¯ Enhanced peristalsis
¯
Watery diarrhea
C. Secretory diarrhea due to excessive stimulation of the secretory cells present in the crypts of
the intestine by enteric pathogenic and/or toxin (infective diarrhea)
1. Inflammatory diarrhea
Pathogens invade the intestinal mucosa and/or elaborate toxins
e.g. invasive and cytotoxin-producing Salmonella
2. Non-inflammatory diarrhea
Pathogens colonize the intestinal lumen and/or produce toxins
e.g. enterotoxins from Vibrio cholerae and certain strains of E. coli. Cf. pancreatic cholera, a form of
tumor producing abnormal amount of VIP (see CC of Lecture 2)
4.2.1. Mechanisms for non-inflammatory diarrhea

Secretory diarrhea can be caused by a common sequela of infections by enteric pathogens.
Enterotoxigenic organisms cause net secretion by stimulating intestinal anion secretion and
inhibiting Na+ and Cl- absorption. Cholera toxin, for example, specifically binds to the GM1-
83
ganglioside receptor located at the luminal membrane of enterocytes and activates epithelial
adenylate cyclase following ADP-ribosylation of Gs, the GTP-binding regulatory protein. This in
turn activates active NaCl transport into the intestinal lumen, leading to severe secretory diarrhea
(Fig. 11-3). On the other hand, E. coli heat-stable enterotoxin (STa) binds to the putative guanylin
receptor and activates guanylate cyclase to increase cGMP level in the enterocytes that is
responsible for so-called traveler’s diarrhea (Fig. 11-4).
(I). The effect of cholera toxin in stimulating intestinal anion secretion and inhibiting Na+ and Cl-
absorption
Fig. 11-3. Mechanism for causing net secretion by cholera toxin.
(II). The effect of enterotoxigenic E. coli in stimulating intestinal anion secretion and inhibiting
Na+ and Cl- absorption
Fig. 11-4. Mechanism for causing net secretion by E. coli heat-stable enterotoxin.
84
4.2.2. Non-inflammatory versus inflammatory diarrhea
Diarrhea from bacteria causes a wide spectrum of symptoms, but can generally be divided into two
types, namely non-inflammatory and inflammatory. In non-inflammatory diarrhea, pathogens
colonize the intestinal lumen and/or elaborate toxins that produce watery diarrhea without blood.
These enterotoxins stimulate secretion but do not harm the mucosal cells. In inflammatory
diarrhea, pathogens invade the mucosa of the intestine and/or elaborate toxins, resulting in the loss
of mucosal integrity and inflammation. This often presents as bloody diarrhea (e.g. in
dysentery and these patients usually have more pronounced systemic symptoms such as fever and
abdominal pain (Table 11-3).
Table 11-3. Comparison of two major clinical diarrhea.

NON-INFLAMMATORY INFLAMMATORY
Clinical manifestations
Watery stools Mucoid and bloody stools

No blood, pus tenesmus or fever May have tenesmus, fever or severe
Abdominal pain not usually prominent abdominal pain
Volume can be large and possible Small volume, frequent bowel movements
dehydration and dehydration unusual
No fecal leukocytes and rarely occult blood Many fecal leucocytes and frequently
occult blood
Causes
Enterotoxin-producing bacteria, minimally Invasive and cytotoxin-producing

Destructive viruses, e.g. microorganisms
Vibrio cholerae e.g.
Enterotoxigenic E. coli Salmonella
Staphylococal & clostridial food poisoning Campylobacter
Rotavirus Invasive E. coli
Norwalk agent Clostridium difficile
Cryptosporidium Amoeba
Giardia Yersinia
4.3. Oral rehydration therapy
One of the most effective treatment of secretory diarrhea is the use of glucose- and amino acid-
containing saline solutions that when administered orally, markedly reduce salt and water losses.
This re-hydration therapy by virtue of oral rehydration/replacement solution (ORS) has
markedly reduced deaths and disabilities attributable to secretory diarrhea worldwide. For the basic
principle for oral re-hydration, please refer to Section 4.3 of Lecture 7 “Mechanism of
glucose/galactose carrier system”. Thus, by adding sugar (e.g. glucose) to oral salt replacement
fluid, one can dramatically increase intestinal absorption of salt and water. Since the function of
the luminal carrier protein, sodium-dependent glucose co-transporter 1 (SGLT1), is intact
and unaffected by secretory diarrhea (non-inflammatory type), hexoses such as glucose will
promote the absorption of sodium and water. With the type of oral formulation, millions of lives
each year are saved.
85
SUMMARY
• GI disorders are usually caused by either by dysfunctions of motility or secretion, which result in
malfunctions of digestion and absorption.
• Disorders of motility affect all major regions of the GI tract. Because GI motility is a complex
result of smooth muscle contraction under neural and hormonal control, abnormal motility can
occur through damage to GI smooth muscle (structural aberration) or to the neurohormonal
mechanisms (functional obstruction) by which it is controlled or to both. Esophageal achalasia is
an example of abnormal neural damage. Two defects in patients with achalasia are demonstrated:
(1) failure of LES to relax, and (2) impaired peristalsis in the body of esophagus. The other
common esophageal dysfunction is GERD (heartburn). This is due to abnormally low LES
pressure. Reflux may also occur if intragastric pressure increases, as may occur after a large meal,
during heavy lifting, or during pregnancy. Similarly, some other GI motor dysfunctions may occur
in the stomach including dumping syndromes and gastroparesis during gastric emptying.
• Disorders of secretion can be clinically observed in abnormal production of acid, intrinsic factor
(pernicious anemia), or mucus by the stomach, digestive enzymes and bicarbonate by the pancreas,
bile by the liver, and water and electrolytes by the small intestine in response to secretagogues.
Either elevated gastric acid secretion or diminished mucosal defense can predispose to, for
example, the development of peptic ulcers.
• Imbalance between absorption and secretion of water and electrolyte results in diarrhea. Flow in
the GI tract is a steady state involving fluid secretion into and absorption from the GI lumen. Each
process is controlled by both extrinsic and intrinsic factors. Subtle aberrations in input or output at
any of several levels can result in diarrhea with or without nutrient malabsorption. Thus, an
excessive osmotic load (lactose intolerance), increased secretion (enterotoxins inducing
diarrhea such as in E. coli or Vibrio cholerae), or diminished fluid absorption (celiac sprue)
may result in diarrhea. In addition, the rate of transit or the GI motility through the gut
determines the time available for intestinal absorption of water, and rapid transit can be the sole
cause of diarrhea or can exacerbate pre-existing diarrhea.
• Diarrhea is normally associated with the loss of a large volume of alkaline fluid with a high
concentration of potassium (hypokalemia) that causes dehydration, metabolic acidosis with
its compensatory increase in breathing frequency. Because of dehydration, hypotension is
accompanied and thus heart rate is increased.
• Finally, it is stressed that a wide range of systemic conditions and diseases may produce
symptoms and signs in the GI tract. These include endocrine disorders that alter control of GI tract
functions or which predispose to pancreatitis or peptic ulcer; complications of diabetes mellitus
including neuropathy and ketoacidosis; pregnancy; deficiency disorders including vitamins and so
on.
• Some GI regulators, their physiological functions, site of release, stimulus for release, and their
clinical relevance are summarized in the following Appendix Table (p.88).
86
Case Study 1
A student traveling through Mexico develops acute, severe watery diarrhea without fever or
chills. Stool examination shows no blood, leukocytes, or fat. However, stool cultures are positive
for the pathogenic bacteria, enterotoxigenic E.coli.
Q1. What type of diarrhea does the student have? How do the bacteria cause this diarrhea (Hint: see
Figure 11.4)?
Q2. What do you expect from an intestinal mucosal biopsy of this student?
Q3. How would you treat this student?
Q4. Compare secretory diarrhea-induced by E. coli with those induced by Vibrio cholerae (Hint:
see Figure 11.3).
Case Study 2
A 40-year-old man has increasing symptoms of abdominal bloating, weight loss, and diarrhea.
The latter is characterized as foul-smelling and bulky (typical of fat in the stool, or steatorrhea).
Although the pancreas appears to be anatomically normal, exocrine pancreatic functions are
abnormal, i.e. decreased secretion of pancreatic enzymes and bicarbonate. His gallbladder also
empties poorly after meals. As a result, the patient develops anemia, maldigestion and
malabsorption. A small bowel biopsy shows the following histopathology:
Q1. What disease does this patient have?

Q2. How do you explain the patient’s symptoms and abnormal gut functions (pancreatic exocrine
deficiency)? What is the cause of anemia in this patient?
Q3. Why immune and inflammatory cells are observed in the biopsy?
Q4. How would you treat this patient?
Q5. Discuss the type(s) of diarrhea of this patient.
Critical Thinking
1. Integrate all the basic knowledge you learnt from this GI and other courses to elaborate how a
fatty meal is digested and absorbed starting from the mouth to the anus. What clinical conditions
cause maldigestion and malabsorption of fat?
2. As above, discuss how a meal of carbohydrate and protein occur in our GI system.
87
Appendix Table. Secretory products, actions, site and stimulus for release and disease manifestations of the GI system.
GI Physiological Site of Stimulus for Clinical
Regulators Actions Release Release Manifestations
True Hormones Stimulates acid Gastric antrum Peptides, amino acids, Zollinger-Ellison syndrome;
Gastrin secretion and growth (and duodenum) distention, vagal Peptic ulcer disease
of gastric oxyntic stimulation
gland mucosa
CCK Stimulates gallbladder Duodenum and Peptides, amino acids, long Acute pancreatitis;
contraction and jejunum chain fatty acids, (acid). Chronic pancreatitis
pancreatic enzyme
secretion; inhibits
gastric emptying
Secretin Stimulates pancreatic Duodenum Acid, (fat)
and biliary bicarbonate
secretion; inhibits
gastric acid secretion
& gastric emptying
GIP/GLP-1 Stimulates insulin Duodenum, Glucose, amino acids, fatty Diabetes
release; inhibits gastric jejunum acids
acid secretion
Motilin Stimulates gastric and Duodenum and Unknown Irritable bowel syndrome;
intestinal motility jejunum Diabetic gastroparesis
Candidate Inhibits pancreatic Pancreatic islets of Protein, (fat and glucose)
Hormones bicarbonate and Langerhans
Pancreatic polypeptide enzyme secretion
Enteroglucagon Elevates blood glucose Ileum Glucose and fat
Paracrines Inhibits release of most GI tract mucosa Acid stimulates and vagus Gallstones
Somatostatin other peptide and pancreatic inhibits release
hormones islets of
Langerhans
Prostaglandins Promote blood flow, Multiple sites Various NSAID-induced gastritis;
increase mucus and of Peptic ulcer disease
bicarbonate secretion GI tract
from gastric mucosa
Histamine Stimulates gastric acid Oxyntic gland Unknown Inflammatory bowel disease;
secretion; mucosa; Celiac disease
Inflammatory reactions Various
immunocytes
Neurocrines Relaxes sphincters and Mucosa and Enteric nervous system Secretory diarrhea;
VIP gut circular muscle; smooth muscle of Pancreatic cholera;
stimulates intestinal gastrointestinal Achalasia
and pancreatic tract
secretion
NO Inhibits mucosal Mucosa and Enteric nervous system Motor and secretory disorders
secretion and relaxes smooth muscle of
GI sphincters gastrointestinal
tract
GRP or Bombesin Stimulates gastrin Gastric mucosa Enteric nervous system
release
Enkephalins Stimulates smooth Mucosa and Enteric nervous system
muscle contraction; smooth muscle of
inhibit intestinal gastrointestinal
secretion tract
Other Regulators Binds vitamin B12 Parietal cells of Constitutive secretion Autoimmune destruction;
Intrinsic factor to facilitate its the stomach resulting in pernicious anemia
absorption
Mucin Lubrication and Goblet cells along Gastrointestinal tract Viscid mucus in cystic fibrosis;
protection entire irritation Attenuation in some cases of
gastrointestinal peptic ulcer.
tract mucosa
Acid Prevents infection; Parietal cells of Gastrin, histamine, Acid-peptic disease
initiates digestion the stomach acetylcholine, NSAIDs
(indirectly)
*The table is modified from Pathophysiology of Disease, McGraw-Hill Companies, 2000.
88

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GI-HUF1 PS LEUNG 2018-2019

GASTROINTESTINAL PHYSIOLOGY 2018 - 2019

MEDU2400 Human Function 1 - GI Physiology

LECTURE 1: Overview of GI System

2. Structural features of the GI tract

*Gut Endocrine System

3. Gut-Associated Lymphoid Tissue (GALT)

Peyer patches or lymphoid nodules

Diffuse or migrating immune cells

Immunologically, GALT, a part of the body’s Mucosa-Associated Lymphoid Tissues (MALT)

Liver Hepatocytes Bile salts

• Motor activity: chewing, swallowing, mixing, propulsion and storage

In addition, GALT contributes significantly to gut immune function. Regulation of GI functions

1. Tips on GI Embryology and GI Histology

INTESTINAL BLIND LOOP SYNDROME

INFLAMMATORY BOWEL DISEASE (IBD)

Resolution: Irritable Bowel Syndrome (IBS)

• Compare and contrast IBS with IBD

LECTURE 2: Regulation of Gastrointestinal Function

2. Basic mechanisms that control the GI motility and secretion

• Distension (luminal contents)

4. Innervation of the GI tract

• Extrinsic (autonomous) nervous system: parasympathetic and sympathetic divisions

- Myenteric plexus controls mainly the GI movements (smooth muscle activity)

4.1. Extrinsic nervous system

4.2. Intrinsic nervous system

Relay to CNS Via ANS Back to ENS

5. Pathways for neurohumoral regulation

Regulatory peptides may be released as neurotransmitters, paracrine/autocrine transmitters, or

• All GI hormones are peptides

5.1. Endocrine pathway

Four criteria must be met for “true hormones”:

Hormones Actions Release sites Stimuli

5.2. Paracrine pathway

- The only GI peptide that functions physiologically as a paracrine

5.3. Neurocrine pathway

• Vasoactive intestinal peptide (VIP)

• Gastrin releasing peptide (GRP) or Bombesin

The following are some of the key points of this lecture:

Functions and regulation of GLP-1:

GLP-1 based therapy for diabetes

Resolution: Pancreatic Cholera

LECTURE 3: Gastrointestinal Motility

1.1. Characteristics of smooth muscle

- Smooth muscle is made of small, narrow and spindle-shaped cells

2. Three regulatory mechanisms that control the gut motility

2.1. Neural control

2.2. Hormonal control

2.3. Myogenic control system

• Mixing of ingested food with digestive secretions and enzymes

Fig. 3-1-2. Segmentation movements Fig. 3-1-3. Peristaltic contraction

3.2.1. Mechanism of peristaltic reflex

CONTRACTION Above ¬ Point of Stimulation ® Below RELAXATION

3.3. Tonic contraction

- Complete tonic contraction is normally found in the GI tract sphincters

3.4. Migrating motor complex (MMC)

4.1. Three principal motor functions of esophagus

4.2. Regulation of esophageal motility

5.1. Three major motor functions of the stomach

5.2. Regulation of gastric emptying

GIP CCK S. Reflex

6.1. Motility of small intestine

6.2. Motility of large intestine