section 12.2
Gastrointestinal Hormones
207
Peptic Ulcer Disease
Peptic ulcers are caused by an imbalance of acid secretion
by the parietal cells and lack of mucosal protective bar-
riers. There are two major causes of peptic ulcer disease.
One is drug induced and the other is caused by a bacterial
infection. The drugs that are related to
gastropathy
(and
also possibly renal insufficiency) belong to a group of com-
pounds known as
nonsteroidal anti-inflammatory drugs
(NSAIDs). NSAIDs encompass many different classes
of chemical compounds including aspirin (acetylsalicylic
acid). NSAIDs exert anti-inflammatory action and are used
in the treatment of many rheumatic conditions. The mech-
anism of action of NSAIDs involves inhibition of the
cyclooxygenase group of enzymes which are responsible
for the synthesis of prostaglandins (Chapter 18). The in-
hibition of those enzymes by aspirin is irreversible and is
caused by covalent modification involving acetylation of
a key serine residue of cyclooxygenase.
At least two isoforms of cyclooxygenase (COX) are
known, COX1 and COX2. COX1 is a constitutive enzyme
and is responsible for the synthesis of prostaglandins that
are essential for normal function. Gastric prostaglandins
maintain mucosal integrity by modulating parietal cell acid
production, stimulate mucus and bicarbonate production
in the mucous gel layer, and regulate mucosal blood flow.
COX2 is induced during inflammation by cytokines and
inflammatory mediators. NSAIDs inhibit both COX1 and
COX2. While they produce a desirable therapeutic effect
as anti-inflammatory agents, NSAIDs undesirably inhibit
the glandular prostaglandin production necessary for nor-
mal function. Thus, drugs that selectively inhibit COX2
enzymes are better anti-inflammatory agents; one such
NS AID is celecoxib (Chapter 18). A stable analogue of
prostaglandin Ei, misoprostol has cytoprotective effects
in the treatment of peptic ulcer disease. Aspirin has other
pharmacological effects such as inhibition of platelet ag-
gregation (Chapter 36).
Peptic ulcer disease is associated with
Helicobacter
pylori
infection in 90% of patients with gastric and duo-
denal ulceration. Elimination of
H. pylori
infection with
antibiotics heals the peptic ulcer and the associated symp-
toms. Combination therapy with antibiotics, anti-secretory
agents, namely H2-receptor antagonists or proton pump
inhibitors, and bismuth salts has significantly improved the
clinical outcome of peptic ulcer disease. Not all strains of
H. pylori
cause peptic ulcer disease, and other factors are
necessary for
H. pylori
colonization and disease to occur.
Flagellated motile bacteria resist peristalsis and adhere to
gastric epithelium in a highly specific manner.
Several adhesins and their ligands have been identified
on the host cells. Lewis blood group antigen has been
identified as an epithelial cell receptor for
H. pylori
binding
(Chapter 10). Enhanced acid production due to chronic
H. pylori
infection has been attributed to the production of
inflammatory mediators (e.g., cytokines, Chapter 35) and
pH alterations. Urease produced by the bacteria converts
urea to ammonia and carbon dioxide. Ammonia increases
the pH and is essential for the survival of bacteria at acidic
pH. A change in pH toward alkalinity may increase the
levels of gastrin, thus causing increased acid production
and a vicious cycle. Urease activity is conserved among all
H. pylori
species as is the primary structure of the enzyme.
H. pylori
organisms that produce vacuolating cytotoxin
(coded by the gene
vacA)
and a high-molecular-weight
protein known as CagA (coded by the gene
cagA)
are im-
plicated in ulcerogenesis and gastritis.
H. pylori
strains
are genetically diverse, due to their ability to mutate and
the ease with which they exchange genes.
H. pylori
infec-
tion may also be a risk factor in adenocarcinoma of the
antrum and the body of the stomach and
non-Hodgkin’s
lymphoma
of the stomach.
Infection by
H. pylori
is detected by serological markers
produced by host immune responses (e.g., antibodies to
antigens of
H. pylori)
and a breath test. The latter, known
as the urea breath test, consists of oral administrations of
radioactively labeled urea. This is metabolized to labeled
C 0
2
and ammonia by the urease of
H. pylori
present in the
gastric mucosa. The presence of labeled C 0
2
measured in
the exhaled air confirms infection.
H2-receptor antagonists and proton pump inhibitors
are used to reduce gastric acidity and are useful in the
treatment of
gastroesophageal reflux disease
(GERD).
In GERD, the contents of the stomach reflux into the
esophagus and is the most common malady of the esopha-
gus. Therapy also involves increasing of lower esophageal
sphincter tone. Surgical therapy involves strengthening
esophageal sphincters by wrapping part of the stom-
ach around lower esophagus and placing pressure on the
sphincter to assist its closure. This procedure, known as
fundoplication,
can be performed by abdominal surgery
or, more commonly, by laparoscopy. GERD complications
involve structures contiguous to the esophagus namely
laryngeal, pharyngeal, pulmonary, sinusal and dental dis-
orders. Lifestyle changes that can alleviate GERD in-
clude cessation of smoking and consumption of alcohol;
avoidance of spicy food, coffee, and bedtime meals; cor-
rection of obesity; and elevation of the head by at least
15 cm (about
6
inches) during sleep. Therapeutic agents
that contain theophylline, anticholinergic agents, and
progesterone should be avoided because they delay gas-
tric emptying and decrease lower esophageal sphincter
tone. One of the changes of chronic GERD that may oc-
cur in some patients is that the healing epithelium of the
