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302 Part 4 Gastrointestinal and endocrine disorders
Hypothalamus
_
Releasing hormones
e.g. CRH
_
+
Anterior pituitary
Trophic hormones
e.g. ACTH
_
+
Gland/organ
e.g. adrenal gland
Hormone released
e.g. cortisol
+
Final effect
e.g. inhibition of cytokines
Figure P4.3 Feedback loops in the endocrine system. CRH, corticotrophin-releasing
hormone; ACTH, adrenocorticotropic hormone; , inhibits; , increases/enhances.
The endocrine pancreas is not under the influence of hormones from the pituitary. It
secretes the hormones insulin and glucagon, critical to the control of blood glucose levels
(see Chapter 14). The pancreas additionally has exocrine functions, excreting enzymes
into the gut lumen that enable the digestion of food (see above and Chapter 12).
P4.2.1 Control of hormone secretion
The release of most hormones in the endocrine system is controlled by a series of
feedback loops. These feedback circuits generally have a negative effect (i.e. reduce
further excretion as levels rise) and can occur at a number of levels (see Figure P4.3). This
constant feedback ensures that hormone levels are maintained within normal ranges;
derangement of this system can lead to pathological states such as thyroid disease (see
Chapter 15, Section 15.2).
P4.2.2 Mechanism of action of hormones
The mechanism of action of various hormones is determined largely by their general
molecular structure. Broadly speaking, hormones can be divided into lipid-soluble and
water-soluble hormones. The lipid-soluble hormones are steroids such as cortisol,
oestrogen and progesterone, and the thyroid hormones. Water-soluble hormones include
proteins and peptides such as insulin, growth hormone, and prolactin.
P4.2 Structure and function of the endocrine system 303
The fat-soluble hormones can generally cross the plasma membrane of cells and have
their effects by binding to intracellular receptors, within either the cytoplasm or nucleus
of the cell. Most of the effects of these hormones are achieved by alterations in the levels
of gene transcription. (Some more immediate non-genomic effects are also coming to
light.) The water-soluble hormones cannot cross the plasma membrane, and so have
their effects by stimulating receptors on the cell surface, of which there are a number of
classes (see Chapter 2, Section 2.2.1). The effects of binding are transmitted into the cell
through second-messenger systems specific to the activated receptor, such as
increases or decreases in cyclic AMP levels, or increases in Ca
2 +
levels. Table P4.2 gives
the source and summarizes the actions of many of the hormones encountered in the
following chapters.
Table P4.2 Source and main actions of common water-soluble and lipid-soluble hormones
Hormone Source Main action
Water-soluble hormones
Adrenocorticotropic hormone Anterior pituitary Increases steroid production from adrenal gland
Follicle stimulating hormone Anterior pituitary Stimulates follicle development in women and sperm
production in men
Growth hormone Anterior pituitary Promotes body growth and development
Luteinizing hormone Anterior pituitary Stimulates production of sex hormones in women and
production of testosterone in men
Prolactin Anterior pituitary Controls milk production
Thyroid stimulating hormone Anterior pituitary Stimulates release of thyroid hormone
Somatostatin Hypothalamus Inhibits release of growth hormone from the anterior pituitary
Thyrotrophin-releasing hormone Hypothalamus Promotes release of TSH from the anterior pituitary
Glucagon Pancreas Increases blood glucose levels
Insulin Pancreas Decreases blood sugar levels
Antidiuretic hormone Posterior pituitary Controls water and electrolyte balance
Oxytocin Posterior pituitary Promotes uterine contraction and milk ejection
Lipid-soluble hormones
Cortisol Adrenal gland Controls protein, carbohydrate, and lipid metabolism; protects
body from stresses
Oestrogen Ovaries Develops female reproductive organs
Progesterone Ovaries Prepares uterus for pregnancy and mammary glands for
lactation
Testosterone Testes Develops the male reproductive organs
Thyroxine Thyroid Controls metabolic function in cells
TSH, thyroid stimulating hormone.
Chapter 12
Upper gastrointestinal tract
disorders
Useful terms for this topic
Chemoreceptor trigger zone: Area of the
brainstem which receives signals that promote
vomiting.
Dyspepsia: Indigestion—persistent or recurrent pain or
discomfort in the upper abdomen.
Emesis: The act of vomiting.
Enterochromaffin cells: Secretory cells in the mucosal
lining of the digestive tract that secrete serotonin
(5-hydroxytryptamine).
Enterochromaffin-like cells: Secretory cells in the
gastric glands that secrete histamine.
Lower oesophageal sphincter: Ring of smooth muscle
at the base of the oesophagus where it enters the
stomach.
In this chapter we examine some conditions aecting the
upper regions of the gastrointestinal tract—the section of
the digestive system from the mouth through to the
stomach. e commonly experienced symptoms of
heartburn, acid regurgitation, and indigestion
(dyspepsia) arise from disturbances of acid secretion in
the stomach and the consequent damage to the mucosal
lining of the oesophagus, stomach, or duodenum. In
Workbook 9 at the end of this chapter we meet Carter, a
G-cells: Secretory cells in the gastric glands that secrete
gastrin.
Gastro-oesophageal reflux disorder (GORD):
Symptoms arising from the reux of acid into the
oesophagus from the stomach, most usually heartburn,
and regurgitation.
Parietal cells: Acid-secreting cells of the stomach wall.
Peptic ulcer: A lesion in the mucosal lining of the
stomach or duodenum caused by the digestive actions
of pepsin and gastric acid.
Proton pump: Integral membrane protein which actively
pumps H+ ions into the stomach lumen.
Somatostatin: Locally acting hormone which inhibits
gastric acid secretion.
doctor whose stressful and unhealthy lifestyle contributes
to persistent and severe gastrointestinal problems, and
who develops a gastric ulcer as a result of infection with
the bacterium Helicobacter pylori.
In order to understand the various treatments available to
relieve the symptoms of acid hypersecretion, we must
rst appreciate how the secretion of acid into the stomach
lumen is regulated.
12.1 Structure of the gastrointestinal wall
As outlined in Section P4.1 in the Introduction to Part 4,
the upper gastrointestinal tract describes the section from
its start (the mouth) through to the stomach. roughout
its length, from the mid-oesophagus onwards, the
generalized structure of the wall of the gastrointestinal
tract is essentially the same. As shown in Figure 12.1, the
wall has four layers.
1. Mucosa: Itself divided into three layers, the mucosa
encompasses the epithelial cell layer, a mucous
membrane which lines the gut lumen and contains
306 Chapter 12 Upper gastrointestinal tract disorders
Figure 12.1 Structure of the gastrointestinal tract wall.
The four layers of the gastrointestinal wall are shown: mucosa, submucosa, muscularis externa,
and serosa. The mucosa is subdivided into the epithelial mucous membrane, lamina propria, and
muscularis mucosa. This generalized structure is seen throughout the gastrointestinal tract, from
midway down the oesophagus through to the anus.
Adapted from Pocock G, Richards CD, Richards DA, Human Physiology (4th edn), 2013. By permission of
Oxford University Press.
specialized cells that secrete digestive juices and
protective mucus. Beneath this, the lamina propria is a
thin middle layer of connective tissue inltrated by small
blood vessels, nerve bres, and lymph ducts. Outermost
is a thin layer of smooth muscle, the muscularis mucosa.
2. Submucosa: A thick layer of connective tissue that
gives the digestive tract its elasticity. It contains larger
blood vessels and lymph ducts, and houses the nerve
bres that make up the submucosal plexus (see
Section P4.1.1 in the Introduction to Part 4).
3. Muscularis externa: e major muscle layer of the
digestive tract. In most areas it consists of a thicker inner
layer of circular muscle, which contracts to produce a
narrowing of the gut lumen, and a thinner outer layer of
longitudinal muscle, which contracts to shorten the
tube length. e action of these two sets of muscles
provides the movements which mix the gut contents,
and propel it forward. A second neural network, the
myenteric plexus, is located here, and regulates motility.
4. Serosa: A thin layer of connective tissue that secretes a
watery uid providing lubrication and preventing
friction. e serosa is connected to the abdominal
walls by thin sheets of connective tissue. is
attachment provides support for the digestive tract
within the abdominal cavity, but is suciently loose to
allow the necessary movement.
12.2 The stomach
e stomach is a J-shaped hollow structure whose
main function is to store ingested food so that it
can be passed into the small intestine at a rate which
allows optimal digestion and absorption. e process of
digestion starts in the stomach, with hydrochloric
acid dissolving and denaturing food molecules.
Contractile movements pulverize the stomach’s
contents and mix the gastric juices to produce
12.2 The stomach 307
Direction of food
Figure 12.2 Regions of the stomach.
chyme, a thick liquid which is then emptied into the
duodenum.
As shown in Figure 12.2, the stomach is divided into four
regions which have distinct functions.
• Cardia—the area where the oesophagus empties into
the stomach. e stomach contents are prevented from
entering the oesophagus by contraction of the lower
oesophageal (or gastro-oesophageal) sphincter, a circle
of smooth muscle at the base of the oesophagus.
• Fundus—lying higher than the oesophageal opening,
this pouch-like region allows gases, formed as byproducts, to collect and combine.
• Body (or corpus)—the main part of the stomach, with
relatively thin muscle walls. e peristaltic waves of
contractile activity are initiated here, but are not
powerful enough to mix the contents of the stomach
eectively.
• Antrum (or pylorus)—the thicker muscular walls in this
region at the base of the stomach contract strongly to
mix food together with gastric secretions (see below) to
form chyme. e contractile movements also propel
the contents towards the duodenum (the rst section of
the small intestine). Entry of chyme into the small
intestine is regulated by the pyloric sphincter, a ring
of smooth muscle at the base of the stomach. is
sphincter regulates the rate at which chyme leaves
the stomach, as well as preventing passage of particles
over a certain size.
Cardia
Lower oesophageal
sphincter
Fundus
PylorusPyloric sphincter
Body
12.2.1 Gastric secretions
e mucosal lining of the stomach contains specialized
cells which secrete the constituents of the gastric juices.
ese secretions work together with the physical mixing
of food in the stomach to generate chyme. e secretory
cells are collected together in gastric crypts—deep
infoldings of the mucous membrane that project down
into the mucosal layer (Figure 12.3). e upper parts of
the crypts are known as gastric pits, and the lower parts
comprise the gastric glands. Four main components of
gastric juice are produced.
• Hydrochloric acid produced by parietal cells
(see Box 12.1) within the gastric glands. e acid
has a number of roles, helping to denature and
break down proteins, and being necessary for the
conversion of pepsinogen to pepsin (see below). It
also has a protective role destroying many bacteria
and other micro-organisms.
• Intrinsic factor is also secreted by parietal cells and is
essential for the absorption of vitamin B12.
• Pepsin is a proteolytic enzyme that initiates the
digestion of proteins. It is produced from the
precursor pepsinogen, released from chief cells; this
conversion requires exposure to HCl which cleaves o
a fragment of the molecule to form pepsin. e
activity of pepsin itself is greatest in an acid
environment.
• Mucus is secreted by cells in the gastric pits, and has a
protective role (see below).
12.2.2 Regulation of secretion of gastric
juices
e production of acid by parietal cells is regulated by a
number of factors released by additional secretory cells
within the gastric glands.
1. Histamine, a basic amine formed from histidine, is
produced by enterochroman-like (ECL) cells
located at the base of the gastric glands. It is stored in
granules and released in response to stimulation of the
cells by acetylcholine (ACh) released from enteric
neurons, and gastrin arriving in the blood (see below).
Histamine is a paracrine mediator (local hormone; see
Figure P4.2 in the Introduction to Part 4) acting locally
on parietal cells, which are thereby stimulated to
secrete acid. e histamine receptors present on
parietal cells are of the H2 subtype. (e location and
function of the dierent histamine receptor subtypes
308 Chapter 12 Upper gastrointestinal tract disorders
Mucus cell
produces mucus
and bicarbonate
Gastric pit
Parietal cell
produces hydrochloric
acid and intrinsic
factor
Chief cell
releases
pepsinogen
G cell
secretes gastrin
Enterochromaffinlike cell
secretes histamine
D cell
secretes somatostatin
Figure 12.3 Organizationofsecretorycellswithinagastriccrypt.
A gastric crypt is a descending projection of the mucosal membrane lining the stomach’s lumen. The upper part,
the gastric pit area, is the site of mucus production. The lower part, the gastric gland region, contains the
secretory cells indicated.
Gastric gland
12.2 The stomach 309
are shown in Chapter 10, Table 10.2.) H2 receptors are
G-protein-coupled receptors, coupled through Gs to an
increase in adenylyl cyclase activity (see Chapter 2,
Section 2.2.3). e resulting raised level of cyclic AMP
stimulates acid secretion by parietal cells by increasing
the number of proton pump molecules on the cell
surface (see Box 12.1).
e release of histamine from ECL cells is inhibited by
prostaglandin E2, a cytoprotective local mediator
generated by most, if not all, cells in the gastric mucosa
(see Section 12.2.3).
2. Gastrin is a polypeptide endocrine molecule secreted
into the bloodstream by G-cells located in the antrum
region at the base of the stomach. Secretion of gastrin is
stimulated by the presence of digested protein in the
stomach, by distension of the stomach, and by
gastrin-releasing peptide, released from cholinergic
nerves innervating the G-cells. It stimulates receptors
on parietal cells coupled to increases in cytosolic Ca2+
concentration (Gq-coupled receptors; see Chapter 2,
Section 2.2.3). is promotes the insertion of additional
proton pump proteins into the plasma membrane of
the parietal cell (see Box 12.1). Gastrin also promotes
acid production indirectly by stimulating receptors on
ECL cells, enhancing their release of histamine. During
the digestion of a meal, gastrin is the principal factor
increasing acid secretion. Gastrin has additional roles
to promote growth of the mucosal cells lining the
stomach and small intestine, thereby helping to
maintain a healthy digestive tract. It also promotes
gastric emptying, promoting the passage of chyme into
the duodenum, the rst section of the small intestine.
3. Somatostatin is a peptide hormone secreted by
D-cells located in gastric glands and in the duodenal
mucosa. Its release is signalled by the high gastric
acidity. is occurs when the stomach empties, and
the acidity of accumulating gastric juices is no longer
buered by the presence of food. Somatostatin acts
locally as a negative paracrine regulator of acid
secretion, through direct action on parietal cells and
by indirect action on ECL and G cells.
Parietal cell function is also regulated by neuronal inputs
from the submucosal plexus and post-ganglionic
parasympathetic neurons. ese cholinergic bres
release ACh which acts on Gq-coupled M3 receptors on
the parietal cells; the increase in cytosolic Ca2+ results in
increased acid secretion (see Box 12.1).
e various regions of the stomach show dierences in
the proportion of secretory cells. e gastric glands in the
mucosa lining the body and fundus areas contain cells
secreting mucus, acid, pepsinogen, and histamine. ose
in the antrum chiey secrete histamine, gastrin, and
somatostatin.
Table 12.1 summarizes the secretory products of the cells
of the gastric mucosa.
12.2.3 Protecting the stomach cells from
digestion
To prevent the gastric juices from acting on the cells lining
the stomach, a number of protective mechanisms are in
place.
1. e surface epithelial cells and mucus cells produce
alkaline mucus, which forms a gel-like protective layer.
Table 12.1 Products of the secretory cells of the gastric mucosa
Secretory cell type Product secreted Stimuli for secretion Function of secretory product
Parietal cell Hydrochloric acid ACh, gastrin, histamine Denatures proteins, activates pepsinogen, kills
micro-organisms
Intrinsic factor Absorption of vitamin B
Mucus cell Alkaline mucus Mechanical stimulation by
stomach contents
Chief cell Pepsinogen ACh, gastrin Activated to pepsin—initiates protein digestion
Enterochromaffin-like cell Histamine ACh, gastrin Stimulates acid secretion from parietal cells
G-cell Gastrin ACh, presence of proteins Stimulates acid secretion from parietal cells, and
D-cell Somatostatin Acid Inhibits acid secretion directly through parietal
ACh, acetylcholine; ECL, enterochromaffin-like
Protection of mucosal layer
histamine secretion from ECL cells
cells, and indirectly through ECL and G cells
12
310 Chapter 12 Upper gastrointestinal tract disorders
Stomach
Box 12.1
Regulation of hydrochloric acid secretion by parietal cells
lumen
Cl
–
+
K
+
H
Secretory
canaliculus
4
H2OCO
3
cAMP
P
+
+
K
+
H
+
9
2+
Ca
+ +
3
5
Parietal
cell
2
Carbonic
anhydrase
1
H2CO
–
Cl
–
HCO
3
–
10 8 7 6
2
GAChHS
ECL cells
–
Blood
HCO
3
S
Figure a
1. Parietal cells contain high concentrations of carbonic anhydrase. This enzyme accelerates the reaction between
CO2 and H2O to generate carbonic acid (H2CO3), which then dissociates into H
2. HCO
3. Cl– is secreted into the stomach lumen across the luminal (or apical) membrane. The Cl– channel involved has yet
4. H + from the dissociation of carbonic acid is actively pumped across the luminal membrane of the parietal cell by
5. K
6. Parietal cells express M3 receptors which are activated by acetylcholine (ACh) released from innervating
–
is exchanged with Cl– from the blood in a nearby vessel via an antiporter mechanism in the parietal cell’s
3
basolateral membrane.
to be elucidated.
the proton pump (H +/K
lumen against a concentration gradient. The proton pump is irreversibly blocked by proton pump inhibitors (e.g.
omeprazole).
+
leaves the cell through channels in the luminal membrane, maintaining the K+ concentration inside the parietal
cell, and providing the proton pump with substrate.
parasympathetic and enteric neurons. These receptors are coupled to an increase in cytosolic Ca
also stimulates the release of histamine from enterochromaffin-like cells (not shown).
+
ATPase) in exchange for K+. The pump drives H
Cholinergic neurons
G
+
and bicarbonate ions (HCO
+
out of the cell and into the stomach
G cells
D cells
2 +
levels. ACh
–
).
3
12.3 Disorders of the upper gastrointestinal tract 311
Box 12.1 Regulation of hydrochloric acid secretion by parietal cells
7. Gastrin, released into the blood from endocrine G-cells, stimulates parietal cell receptors coupled to increased cytosolic
2 +
Ca
levels.
8. Histamine is released by paracrine enterochromaffin-like cells, and stimulates H2 histamine receptors on the nearby
parietal cells. Activation of these Gs-coupled receptors leads to an increase in cyclic AMP levels inside the cells. H2receptor antagonists (e.g. ranitidine) competitively inhibit the actions of histamine at these receptors.
9. The elevation in cyclic AMP and Ca
the luminal membrane of the parietal cell. Ready-formed proton pumps are present in parietal cells, inserted in membranes
of intracellular vesicles. When the cells are stimulated the vesicle membrane fuses with the luminal plasma membrane, and
the proton pumps are transferred. They are specifically inserted in secretory canaliculi—deep channels in the
membrane of the activated cell, where they participate in acid secretion.
10. The hormone somatostatin, released from D-cells (or cells) in the gastric glands, acts at receptors on the parietal cells to
inhibit their secretion of acid. Its receptors are Gi-coupled, leading to a decrease in cyclic AMP levels. Somatostatin also
acts on enterochromaffin-like cells and G-cells to inhibit the release of histamine and gastrin, respectively, thereby
indirectly inhibiting acid secretion still further.
ACh, acetylcholine; ECL cells, enterochromaffin-like cells; G, gastrin; H, histamine; S, somatostatin.
2 +
mediated by these factors increases the number of active proton pump molecules in
Bicarbonate ions are secreted into the mucus layer and
are trapped, neutralizing the eect of hydrochloric acid
in the immediate vicinity of the cell surface.
(Paradoxically, this protective mechanism allows the
bacterium Helicobacter pylori (H. pylori) to thrive at the
mucosal layer surface, sheltered from the harsh
environment of the stomach lumen; see Section 12.3.2.)
2. Prostaglandins, particularly PGE2, act as local
located on cells in the vicinity of release (including that
from which it has been released—autocrine
signalling). e protective roles of prostaglandins
include stimulating mucus and bicarbonate secretion,
and decreasing gastric acid production by inhibiting
the release of histamine from ECL cells.
3. Tight junctions between the mucosal cells prevent the
gastric juices from penetrating the stomach wall.
protective agents. ese signalling molecules are
generated in virtually all cells of the gastric mucosa via
the action of the enzyme cyclo-oxygenase. (is
enzyme is the molecular target of non-steroidal
anti-inammatory drugs; NSAIDs.) As a lipid entity,
PGE2 readily diuses across the plasma membrane to
stimulate G-protein-coupled receptors (EP receptors)
4. e integrity of the mucosal barrier is maintained by
rapid turnover of cells. Damaged cells are replaced
through division of stem cells within the gastric pits. e
daughter cells produced either migrate out of the pit area
and become surface epithelial cells, or migrate to the
gastric gland region and dierentiate into secretory cells.
12.3 Disorders of the upper gastrointestinal tract
Conditions aecting the upper gastrointestinal tract are
among the most prevalent illnesses in Western countries;
the two most common are discussed here.
12.3.1 Gastro-oesophageal reflux disease
e most common condition aecting the upper
gastrointestinal tract is gastro-oesophageal reux disease
(GORD). is describes any symptom arising from
episodes of acid reux into the oesophagus from the
stomach, most usually retrosternal pain (heartburn) and
regurgitation. Damage to the lower reaches of the
oesophagus caused by exposure to the stomac acid leads
to inammation. Over time structural changes can occur,
with the development of strictures (narrowings) which
give rise to dysphagia (diculty in swallowing). e
peristaltic movements in the oesophagus may also be
altered. e suerer is predisposed to a number of
conditions, including oesophageal cancer. People who
suer repeated episodes of gastro-oesophageal reux
should be encouraged to seek medical advice.