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Objectives of study

1. To define peptic ulcer

2. To discuss the complications and causes of peptic ulcer
3. To describe the mechanism of gastro-protection


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

- 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:

Gastric: 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 asymptomatic.

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
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

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 pain-causing
foods, is unnecessary in ulcer patients.

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
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.

Depends on the type and cause, which could include; Proton pump inhibitors, Histamine blockers,
Antibiotics, Antacids,(to neutralize acids) 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 mucus-
bicarbonate 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 acid-
and 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 factor-alpha (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

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

B. Neurohormonal/neuroendocrine 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.

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