LECTURE 4: PEPTIC ULCER AND GASTROPROTECTION
PEPTIC ULCER:
Is defined as a break in the mucosa, which extends through the muscularis mucosae, and is
surrounded by acute and chronic inflammation. The lesion of peptic ulcer disease (PUD) is a
disruption in the mucosal layer of the stomach or duodenum (gastric or duodenal ulcer
respectively).
An ulcer is distinguished from erosion by its penetration of the muscularis mucosa or the
muscular coating of the gastric or duodenal wall.
Peptic ulcer disease results from an imbalance between defensive mechanisms of the mucosa
and
aggressive
factors.
A. Mucosal defence mechanisms-Mucus secretion, bicarbonate production, mucosal blood
flow, cellular repair mechanism, prostaglandin E’s, growth factors, antioxidants system.
B. Aggressive factors: acid/pepsin, bile acids, NSAIDS, H.pylori infection, smoking, alcohol,
stress, coffee, oxidative stress.
Symptoms of peptic ulcer:
Gastic: Epigastric pain accompanied by other dyspeptic symptoms viz; fullness, bloating, early
satiety and nausea.
Duodenal: Epigastric pain relieved by food intake/acid-neutralizing agents, heartburn mostly
without erosive oesophagitis.
Chronic ulcer could be a symptomatic.
Complications of peptic ulcer:
1. Gastrointestinal bleeding: Results when the ulcer erodes into a blood vessel in the wall of
the stomach or duodenum. The common signs of bleeding include: A. Vomiting B. Bright
red blood or passing bloody or tarry, black stools. C. Pepto bismol often taken for relief of
ulcer symptoms may also cause black discolouration of stools. D. In case of severe bleeding,
weakness, fatigue, loss of consciousness, and/or shock may result.
2. Perforation: This can develop as stomach acid erodes through the intestinal wall and spills
into the abdominal cavity. The 1st sign of perforation is sudden, intense, steady, abdominal
pain.
3. Obstruction of digestive tract: Usually at the junction of the stomach and duodenum, ulcer
scars accumulate and narrow the passage way through this area. As a result food and fluid
passing from the stomach to the duodenum may be restricted or blocked altogether,
producing a distended stomach. Intense pain and continued vomiting occur.
Causes of peptic ulcer.
1. Gastric acid, pepsin and bile salt: Injury to gastric and duodenal mucosa develops when
deleterious effect of gastric acid, pepsin and bile salt overwhelm the defensive properties of the
mucosa.
2. Helicobacter pylori: Is the etiologic factor in most patients with peptic ulcer disease and may
predispose individuals to the development of gastric carcinoma; H.pylori colonizes in the
human stomach. It is transmitted from person to person spread through a faecal-oral route; its
prevalence is inversely related to the socio economic status. Water can also be a reservoir for
transmission of H.pylori.
Bacteria factors.
i. Colonisation/Bacterial attachment:
Bacteria motility, urease and its ability to adhere to gastric epithelium are the factors that allow
it to survive in the acidic environment.
-H.pylori is capable of swimming freely within the mucus gel by utilising its polar flagella. It
senses and responds to PH gradients by swimming away from the acidic PH.
-Also its ability to produce large amount of cystolic `and cell surface associated urease makes it
to function at 2 different PH values 7.2 and 3.
Cell surface associated urease hydrolyses gastric luminal urea to ammonia that helps neutralise
gastric and form a protective cloud around the bacterium.
ii. Virulence factors:
H.pylori induced gastritis and damage to the gastric mucosa is probably secondary to immune
recognition of the bacteria and damage from various bacterial products. Various bacterial
products have been described as “toxins” based on biological activity e.g. Vac A and Cag A.
iii. Mechanism of persistence:
In order to colonise the human stomach, H.pylori must overcome the physical and chemical
barriers as well as innate and adaptive immune responses that are triggered in the stomach by
its presence. H.pylori urease functions mainly as protective buffering enzymes against gastric
acidity. Several bacterial factors including catalase and urease antagonise innate host immune
responses. H.pylori produces an enzyme arginase that inhibits nitric oxide production and may
favour bacterial survival.
3. Non steroidal anti-inflammatory drugs (NSAID): The risk factors for the development of
NSAID associated gastric and duodenal ulcers include advanced age, history of previous ulcer
disease, concomitant use of corticosteroids and anticoagulants, higher doses of NSAIDS and
serious systemic disorders.
*NSAIDS initiate mucosal injury topically by their acidic properties by diminishing the
hydrophobicity of gastric mucus. Systemic effects of NSAIDS appear to play a predominant role
through the decreased synthesis of mucosal prostaglandins. The precursor of prostaglandins,
arachidonic acid, is catalysed by the two cyclo-oxygenase isoenzymes; cyclo-oxygenase-1 and
cyclo-oxygenase-2. The gene for cyclo-oxygenase-1, the house keeping enzyme, maintains the
homeostasis of organ. Cyclo-oxygenase-2, the inflammatory enzymes is inducible: Literature
suggests that the anti-inflammatory properties of NSAIDS are mediated through inhibition of
cyclo-oxygenase-2, and adverse effect such as gastric acid, duodenal ulceration, occur as a
result of effects on the constitutively expressed cyclo-oxygenase-1.
4. Gastrinoma (Zollinger-Ellison Syndrome): Is a collection of symptoms which involves; peptic
ulcers in unusual locations (i.e. the jejunum), massive gastric acid hyper secretion and a gastrin
producing islet cell tumour of the pancreas (gastrinoma).
Patients with gastrinoma may have intractable ulcer disease, because gastrin is trophic to the
gastric mucosa, hypertrophy of the gastric rugae, diarrhoea, and gastroesophagus reflux may
also be episodic symptoms in 75% of patient.
5. Hypercalcaemia: Hypercalcemia has a direct bearing on the gastric acid hypersecretory state
found in patients with zollinger-Ellison syndrome. Intravenous calcium infusion in normal
volunteers induces gastric acid hypersecretion; calcium has also been demonstrated in vivo and
in vitro to stimulate gastrin release directly from gastrinomas. Resolution of hypocalcaemia
plays an important role in the therapy of this sub group of patients.
6. Genetic factors: The lifetime prevalence of developing ulcer disease in first degree relatives
of ulcer patients is about 3x greater than the general population. Approximately 20-50% of
duodenal ulcer patients report a positive family history.
7. Smoking: There is a strong positive correlation between cigarette smoking and the incidence
of ulcer disease, mortality complications recurrences and delay in healing rate. Smokers are
about 2x more likely to develop ulcer than non smokers. Cigarette smoking May increase
susceptibility, diminish the gastric mucosal defensive factors or may provide a more favourable
milieu for H. Pylori infection.
8. Stress. Numerous studies have revealed conflicting conclusions regarding the role of
psychological factors in the pathogenesis and natural history of peptic ulcer disease. The role of
psychological factors is far from established. Acute stress results in increases in pulse rate,
blood pressure and anxiety, but only in those patients with duodenal ulcers did acute stress
actually result in significant increases in basal acid secretion.
9. Alcohol and diet: Although alcohol has been shown to induce damage to the gastric mucosa
in animals, it seems to be related to the absolute ethanol administered (200 proof). Pure
ethanol is lipid soluble and results in frank, acute mucosal damage. Because most humans do
not drink absolute ethanol, it is unlikely there is mucosal injury at ethanol concentrations of less
than 10% (20 proof). Ethanol at low concentrations (5%) may modestly stimulate gastric acid
secretions; higher concentrations diminish acid secretion. Though physiologically interesting,
this has no direct link to ulcerogenesis or therapy.
Some types of food and beverages are reported to cause dyspepsia. There is no convincing
evidence that indicates any specific diet causes ulcer disease. Epidemiologic studies have failed
to reveal a correlation between caffeinated, decaffeinated, or cola-type beverages, beer, or
milk with an increased risk of ulcer disease. Dietary alteration, other than avoidance of paincausing foods, is unnecessary in ulcer patients.
Diagnosis
1. By Endoscopy: This test involves passing a fiber optic tube with a camera at its tip into the
stomach and duodenum.
2. Biopsy sample of the antral and body or fundus mucosa. It is taken to detect H. pylori
infection by:
a. Rapid urease test
b. Histological test
c. Immunohistochemical test
3. Urea Breath Test (UBT) and stool antigen test are used in the elderly.
4. Measurement of serum gastrin level
5. Gastric acid secretion test.
Treatments
Depends on the type and cause, which could include; Proton pump inhibitors, Histamine
blockers, Antibiotics, Antacids, e.t.c.
Mechanisms of gastric mucosal defense (Gastro-protection).
The mechanisms of gastric mucosal defense include several local and neurohormonal
protective factors, which allow the mucosa to resist against frequent exposures to damaging
factors. In the following sections, a detailed description of the mucosal defense mechanisms is
provided.
A. Local mechanisms of gastric mucosal defense
1 Mucus-bicarbonate-phospholipids barrier
The first line of gastric mucosal defense is represented by the mucus-bicarbonate phospholipids
barrier. The surface of gastric mucosa is covered by a layer formed by mucus gel, bicarbonate
anions and surfactant phospholipids. This unstirred layer is capable of retaining the bicarbonate
ions secreted by surface epithelial cells and maintaining a microenvironment with a pH near to
7 at the mucus-mucosa interface. The mucus layer is also able to prevent the penetration of
pepsin, thus avoiding the proteolytic digestion of epithelium. In addition, the luminal surface of
mucus gel is covered by a film of surfactant phospholipids which confers hydrophobic
properties to the mucus layer.
The mucus gel is secreted by surface epithelial cells and is formed by a large amount of water
(about 95%) and various kinds of mucin glycoproteins (i.e., MUC2, MUC5AC, MUC5B and
MUC6), the production of which may vary in different regions of the gastric. The secretion of
gastric mucus is regulated also by various gastrointestinal hormones, including gastrin and
secretin, as well as prostaglandins and acetylcholine.
The secretion of bicarbonate into the mucus gel layer is essential to maintain a pH gradient at
the epithelial surface, which represents a first line of defense against gastric acid. The mucusbicarbonate barrier is the only system which segregates the epithelium from the gastric lumen.
Therefore, when this protective barrier breaks down during pathological events or upon
detrimental actions by injuring agents, a second line of protective mechanisms comes into play.
They include intracellular acid neutralization, rapid epithelial repair, and maintenance of
mucosal blood flow.
2. Epithelial cells
The continuous layer of surface epithelial cells represents the next line of mucosal defense. This
epithelial tissue is responsible for the production of mucus, bicarbonate and other components
of the gastric mucosal barrier. These cells are hydrophobic in nature, being able to repel acidand water-soluble injuring agents, owing to the presence of phospholipids on their surface.
Surface epithelial cells are also closely interconnected by tight junctions, forming a continuous
barrier, which prevents back diffusion of acid and pepsin.
Another relevant protective factor, available in the epithelial cells, is represented by heat shock
proteins, which are activated in response to stress, including temperature increments, oxidative
stress and cytotoxic agents. These proteins can prevent protein denaturation and protect cells
against injury. Cathelicidin and beta-defensin are cationic peptides which play a relevant role in
the innate defensive system at the mucosal surface, preventing bacterial colonization.
3. Mucosal cell renewal
The integrity of gastric epithelium is maintained by a continuous process of cell renewal
ensured by mucosal progenitor cells. These cells are subjected to a continuous, well
coordinated and controlled proliferation, which ensures the replacement of damaged or aged
cells on the epithelial surface. The process of complete epithelial renewal takes about 3-7 days,
while the overall glandular cell replacement requires months. However, the restitution of
surface epithelium after damage occurs very quickly (i.e., few minutes) and results by migration
of preserved cells located in the neck area of gastric glands.
The process of cell turnover is regulated by growth factors. In particular, expression of
epidermal growth factor receptor (EGF-R) has been detected in gastric progenitor cells. Such a
receptor can be activated by mitogenic growth factors, such as transforming growth factoralpha (TGF-α) and insulin-like growth factor-1 (IGF-1). In addition, PGE2 and gastrin are able to
transactivate the EGF-R and promote the activation of mitogen-activated protein kinase (MAPK)
pathway, with consequent stimulation of cell proliferation.
4. Mucosal blood flow
Mucosal blood flow is essential to deliver oxygen and nutrients and to remove toxic
metabolites from gastric mucosa. Arteries embedded into the muscularis mucosae branch into
capillaries, which then enter the lamina propria and travel toward the proximity of glandular
epithelial cells. Endothelial cells, lining these microvessels, produce NO and prostacyclin (PGI2),
which act as potent vasodilators, thus protecting the gastric mucosa against damage and
counteracting the detrimental effects of various vasoconstrictors, including leukotriene C4,
thromboxane A2, and endothelin. In addition, NO and PGI2 maintain the viability of endothelial
cells and inhibit platelet and leukocyte adhesion to the microvasculature, thus preventing the
occurrence of microischaemic phenomena.
When the gastric mucosa is exposed to irritants or acid back-diffusion, a massive and rapid
increase in mucosal blood flow occurs. This process allows removal and dilution of back
diffusing acid or noxious agents. The increase in blood flow is regarded as a pivotal mechanism
for preventing gastric mucosal cell injury, and its decrease results in the development of tissue
necrosis.
5. Sensory innervation
The vasculature of gastric mucosa and submucosa is innervated by extrinsic primary afferent
sensory neurons, which are arranged in a plexus at the base of the mucosal layer. The nerve
fibers stemming from this plexus run along with capillary vessels and reach the basal membrane
of surface epithelial cells. These nerves can detect luminal acidity or back-diffusing acid through
acid-sensing channels. The activation of such sensory nerves modulates the contractile tone of
submucosal arterioles, thus regulating the mucosal blood flow. In particular, the stimulation of
sensory nerves leads to the release of calcitonin gene-related peptide (CGRP) and substance P
from nerve terminals surrounding large submucosal vessels. CGRP then contributes to the
maintenance of mucosal integrity through the vasodilation of submucosal vessels mediated by
NO release. Therefore Sensory innervation plays a prominent role in the protection of gastric
mucosa from injury.
6. Prostaglandins
The gastric mucosa represents a source of continuous prostaglandin production, such as PGE2
and PGI2, which are regarded as crucial factors for the maintenance of mucosal integrity and
protection against injuring factors. It has been demonstrated that prostaglandins have the
potential to stimulate almost all the mucosal defense mechanisms. In particular, they reduce
acid output, stimulate mucus, bicarbonate and phospholipids production, increase mucosal
blood flow, and accelerate epithelial restitution and mucosal healing. Prostaglandins are also
known to inhibit mast cell activation as well as leukocyte and platelet adhesion to the vascular
endothelium.
B. Neurohormonal mechanisms
Gastric mucosal defense is supported by mechanisms activated, at least in part, by the central
nervous system and hormonal factors. Experimental studies have demonstrated that central
vagal activation stimulates mucus secretion and increases intracellular pH in the surface
epithelial cells of the stomach.
Other hormone mediators, including gastrin-17, cholecystokinin, thyrotropin-releasing
hormone, bombesin, EGF, peptide YY and neurokinin A, play significant roles in the regulation
of gastric protective mechanisms, which can be blunted by afferent nerve ablation, Ghrelin, a
hormone peptide produced by gastric A-like cells in rodents and P/D1 cells in humans, is
involved in the regulation of growth hormone secretion and appetite stimulation. Moreover, it
is also able to exert significant protective effects at gastric level, including the enhancement of
mucosal blood flow via stimulation of NO and CGRP release from sensory afferent nerves.
Glucocorticoids have been shown to support the mechanisms of protection at gastric level.
These hormones are involved in the response to stress, and represent potent gastro protective
factors against injury. The mechanisms through which glucocorticoids exert their protective
effects include the maintenance of glucose homeostasis, the increase in mucosal blood flow
and mucus secretion, and the attenuation of both enhanced gastric motility and microvascular
Permeability.