Dr. Kiran H S
Assistant professor
Pathology
Definitions
 Erosion: Loss of the superficial epithelium which
produces a small defect in the mucosa that is limited
to the lamina propria (do not penetrate the muscularis
mucosae).
 Ulcer: Break in the mucosal surface more than 5
mm in size, with depth to the submucosa. It leads to
a local defect or excavation due to active inflammation.
Gastric ulcers (GUs) and duodenal ulcers (DUs)
may be acute or chronic.
Gastritis: Inflammation of the gastric mucosa and is
usually a histological diagnosis
A. Depending on the inflammatory cells and duration
 Acute gastritis shows predominately acute
inflammatory cells
 Chronic gastritis shows mononuclear cell
(lymphocytes, plasma cells) infiltration
 – Helicobacter pylori gastritis
 – Autoimmune gastritis
 – Others
B. Depending on the segment of involved stomach
 Antral-predominant gastritis
 Corpus-predominant gastritis
 Pangastritis
C. Depending on the absence or presence of
premalignant stages
 Nonatrophic
 Atrophic gastritis: may progress to carcinoma
ACUTE GASTRITIS
 Acute gastritis is a transient inflammation of gastric
mucosa.
Etiology
 Drugs: Aspirin, NSAIDs and other drugs (e.g. iron
preparations)
 H. pylori
 Alcohol
 Chemicals
 Severe physiological stress (e.g. burns)
 Bile reflux (e.g. following gastric surgery)
 Viral infections (e.g. cytomegalovirus—CMV).
Pathogenesis
 Acute (also chronic gastritis) can develop following disruption of any
of the protective mechanisms.
 Reduced synthesis of mucin (e.g. during old age) increased
susceptibility to gastritis.
 Nonsteroidal anti-infl ammatory drugs (NSAIDs) interfere with
protection provided by prostaglandins or reduce bicarbonate secretion.
 Gastric injury in uremic patients and those infected with urease-
secreting H. pylori may be due to inhibition of gastric bicarbonate
transporters by ammonium ions.
 Ingestion of chemicals (e.g. acids or bases), either accidentally or as a
suicide attempt direct injury to mucosal epitheliums. Direct cellular
injury may also be caused by excessive alcohol consumption, NSAIDs,
radiation therapy, and chemotherapy.
 Insufficient epithelial regeneration following cancer chemotherapy.
 Decreased oxygen supply at high altitudes.
Morphology
 Mild acute gastritis: No significant changes
 Severe gastritis: Severe mucosal damage, erosions
and hemorrhage termed acute erosive
hemorrhagic gastritis.
 Microscopy: It shows, dense infiltration by neutrophils
within the mucosa and purulent exudate in the lumen.
Clinical Features
 May be asymptomatic or cause variable degrees of
epigastric pain, nausea, and vomiting.
 When severe, it causes mucosal erosion, ulceration,
hemorrhage, hematemesis and melena.
PEPTIC ULCER DISEASE (PUD)
 Definition: Peptic ulcer is defined as a mucosal defect that
is at least 0.5 cm in diameter and penetrates the
muscularis mucosae.
 PUD is most often associated with colonization with H.
pylori and H. pylori-induced chronic gastritis (with
hyperchlorhydria).
Components involved in mucosal defense and repair in normal (left side) and
in acute or chronic gastritis(right side). Gastric mucus barrier consists of
viscid mucus (forms an unstirred layer between the epithelium and the gastric
lumen) and bicarbonates
Normal Process in the Stomach
 Two opposing sets of forces keep stomach in a normal state: A. damaging forces and B.
Defensive forces .
A. Damaging Forces
 These forces are capable of inducing mucosal injury and consists of two gastric secretory
products: 1) hydrochloric acid and 2) pepsinogen.
 1. Gastric Acidity
 Hydrochloric acid plays main role in digestion but also can damage the gastric mucosa.
 a. Enzyme H+,K+-ATPase is responsible for producing the large concentration of H+. Acid is
 secreted by the parietal cell located in the oxyntic gland.
 b. Parietal cell expresses receptors for many stimulants of acid secretion, including histamine
 (H2), gastrin (cholecystokinin B/gastrin receptor), and acetylcholine (muscarinic, M3).
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2. Peptic Enzymes
They can also damage the gastric mucosa.
a. Pepsinogen, which is an inactive precursor of pepsin, is synthesized and secreted by the
chief cell, found mainly in the gastric fundus.
b. The acid environment within the stomach leads to conversion of pepsinogen to pepsin and
provides the low pH (<2.0) required for activity of pepsin.
 c. Pepsin activity decreases as the pH increase; it is markedly decreased at a pH of 4 and
 inactivated at a pH of 7 and above. Many of the substances, which stimulate acid secretion,
 also stimulate pepsinogen release.
B. Defensive Forces
 These are a three-level barrier composed of 1) pre-epithelial, 2) epithelial, and 3) subepithelial
elements.
 1. Pre-epithelial Barrier
 It is a mucus-bicarbonate layer of the stomach. It is formed by several factors produced by
surface epithelial cells, such as a) production of mucus, b) bicarbonate secretion, c) epithelial
cell ionic transporters that maintain intracellular pH and and d) intracellular tight junctions.
 a. Surface mucus secretion: Mucin is secreted by surface foveolar cells. Actions of mucus
are:
 – Mucus layer promotes formation of an “unstirred” protective layer of fluid on the
mucosa.
 – Prevents the direct contact of large food particles to the epithelium.
 – Impedes the diff usion of ions and molecules such as pepsin.
 b. Bicarbonate secretion: Surface epithelial cells secrete bicarbonate into the mucus It
results in a pH gradient, ranging from 1 or 2 at the gastric luminal surface, and reaching to a
neutrality of 6 to 7 along the epithelial cell surface.
 2. Epithelial Barrier
 It consists of surface epithelial cells that acts through a) restitution of
damaged gastric epithelial cells, b) epithelial regeneration, c) secretion of
prostaglandins and d) production of mucus
 a. Restitution: It is the process of restoration of a damaged region by
the gastric epithelial cells and requires continuous blood flow and an
alkaline pH in the surrounding environment.
 b. Epithelial regeneration: It is regulated by prostaglandins and
growth factors such as EGF and TGF- beta.
 c. Secretion of prostaglandins: Gastric mucosa secrets prostaglandin
which plays a main role in gastric epithelial defense/repair.
Prostaglandins maintain mucosal blood flow and epithelial cell
restitution.
 3. Subepithelial Barrier
 Rich gastric mucosal blood flow: It provides 1) bicarbonate (HCO3–),
which neutralizes the acid generated by parietal cells, 2) an adequate
supply of nutrients and oxygen, and 3) removes toxic metabolic byproducts.
Pathogenesis of PUD/Acute or
Chronic Gastritis
 The imbalances between mucosal defenses and
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damaging forces cause chronic gastritis and also PUD.
Acute or chronic gastritis or PUD can occur due to
direct mucosal injury or disruption of any of
protective mechanisms.
Direct Mucosal Injury/Increased Damage
1. H. pylori infection is one of the most important,
common, primary cause of PUD.
H. pylori is a Gram-negative spiral bacteria with multiple
flagella at one end. It is associated with ~ 85–90% of
duodenal and ~65% of gastric ulcers.
 Mode of spread: Oro-oral or feco-oral route.
 Lesions produced: H. pylori may attach to gastric
epithelium causing damage to the mucosa.
 Causes chronic antral gastritis with high acid
production may progress to pangastritis resulting
multifocal atrophic gastritis increased risk of gastric
adenocarcinoma.
Mechanism of action by H. pylori:
 – Flagella: It makes them motile, allows it to burrow and live beneath the mucus layer
above the epithelial surface.
 – Urease: Produced by H. pylori releases ammonia (strong alkali) from endogenous
Urea raises the local gastric pH acts on the antral G cells release of gastrin.
Hypergastrinemia result in hypersecretion of gastric acid.
 – Adhesion molecule: It helps it to bind to gastric epithelial (surface foveolar) cells.
 – Enzymes: Th ese include proteases and phospholipases that acts on mucous ge
reduces the mucosal defense.
 – Cytotoxins: Products of two gene namely cytotoxin-associated gene A (CagA) and
vacuolating agent (vacA) gene cause gastritis, peptic ulceration and cancer.
 – Cytokine induces infl ammatory response: Normally H. pylori do not invade the cells/
tissues. It causes increased production of pro-infl ammatory cytokines {interleukin (IL)-1,
IL-6, tumor necrosis factor (TNF) and IL-8} by the mucosal epithelial cells activation of
neutrophils and macrophages (infl ammatory response to gastric mucosa) release of
lysosomal enzymes, leukotrienes and reactive oxygen species impairs mucosal defense. The
cytokines also stimulate gastrin release increased acid production.
 2. Nonsteroidal anti-infl ammatory drugs (NSAIDs) and aspirin: It
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causes 1) direct chemical irritation of mucosa, 2) suppresses mucosal
prostaglandin synthesis and 3) reduces the bicarbonate secretion.
3. Cigarette smoking: Impairs blood flow to the mucosa and healing of
mucosal damage.
4. Alcohol, radiation therapy and chemotherapy: They cause direct
injury to mucosal cells.
5. Ingestion of chemicals: These include acids or bases and cause
direct injury.
6. Gastric hyperacidity: The causes of hyperacidity include H. pylori
infection, parietal cell hyperplasia and Zollinger-Ellison syndrome .
7. Others
High-dose corticosteroids: They suppress prostaglandin synthesis and
impair healing.
Psychologic stress.
Duodenal gastric reflux.
Impaired Defense
 Ischemia: Decreased oxygen delivery (e.g. at high
altitudes and shock)
 Shock
 Delayed gastric emptying
 Host factors: Reduced mucin synthesis in the
elderly increased susceptibility to gastritis.
Morphology- Gross
 Sites of peptic ulcer: They can develop in any portion of the GI
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tract exposed to acidic gastric juices.
1. Duodenum: More common in the first portion of the
duodenum (anterior or posterior wall) than in the stomach.
2. Stomach: Lesser curvature near the junction (transitional
zone) of the body and antrum:
a. Proximal ulcers: Located in the body of the stomach.
b. Distal ulcers: Located in the antrum and angulus of the stomach.
3. GE junction of esophagus.
4. Anastomotic site: It can develop at the anastomotic site in
patients who have undergone a distal gastric resection. Occur at
margins of the gastroduodenal anastomosis/gastrojejunostomy
(anastomotic ulcer).
5. Multiple ulcers: In the duodenum, stomach, and/or jejunum
in Zollinger-Ellison syndrome.
 6. At metaplastic or heterotopic gastric mucosa: e.g.
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Meckel diverticulum within an ileum having ectopic
gastric mucosa.
Number: Solitary in more than 80% of patients, but may
be more than one.
Size: Lesions less than 0.6 cm in diameter are shallow and
those larger than 0.6 cm are likely to be deeper ulcers.
Shape: Round to oval, sharply punched-out defect.
Margin: Usually in level with the surrounding mucosa.
The gastric mucosal folds can be traced up to the margins
of ulcer and the radiating folds of mucosa from ulcer appear
like a spoke wheel.
In contrast, heaped-up margins are more characteristic of
cancers.
Depth: Varies.
Base: It is smooth and clean as a result of peptic digestion
of exudate.
Microscopy
 Gastric and duodenal ulcers are microscopically similar.
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From the lumen outward four layers can be identified
and are known as Askanazy zones.
1. Necrotic zone: It is the most superficial zone.
2. Superficial exudative zone: It consists of
fibrinopurulent exudates with predominantly
neutrophilic inflammatory infiltrate.
3. Granulation tissue zone: It consists of granulation
tissue infiltrated with mononuclear leukocytes.
4. Zone of cicatrization: It consists of fibrous tissue
or collagenous scar which forms the base of the ulcer
and may show chronic inflammatory cells.
Photomicrograph shows
H. pylori (arrows) in the lumen of gastric
glands (A. Giemsa stain; B. WarthinStarry)
Duodenal ulcer in the first part of
duodenum showing characteristic sharp
demarcation from the surrounding
mucosa
Clinical Features
 Peptic ulcers are chronic, recurring lesions with more
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morbidity than mortality.
Age: Young adults but are most often diagnosed in
middle-aged to older adults.
Periodicity: After a period of weeks to months of active
disease, healing may occur with or without treatment.
Pain: Epigastric burning or aching pain exacerbated by
fasting and improved with alkali or food.
Other symptoms: These include nausea, vomiting, bloating,
belching, and significant weight loss.
Complications of Gastric Ulcers
 Bleeding: Most common complication of peptic ulcer.
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Chronic blood loss may lead to iron deficiency anemia.
Severe bleeding may cause “coffee ground” vomitus or
melena and may be life-threatening.
Perforation: Develops in ~ 5% of patients and is the
most common complication of gastric ulcer.
Pyloric obstruction (gastric outlet obstruction): It is
associated with ulcers in the pyloric region and occurs in
~ 10% of ulcer patients.
Rarely malignant transformation: The dictum is that
‘cancers ulcerate but ulcers rarely cancerate’.
Development of combined ulcers: In the stomach and
duodenum in the same patient.
CHRONIC GASTRITIS
 Gastritis is inflammation of stomach associated
with mucosal injury.
 Causes: Common cause of chronic gastritis is due to
infection by Helicobacter pylori.
 Other causes include: chronic irritants, such as
caffeine, alcohol, tobacco use and psychologic stress.
Morphology of H. pylori Gastritis
Microscopy :
 Presence of intraepithelial neutrophils and
subepithelial (superficial lamina propria) plasma
cells are characteristic of H. pylori gastritis.
 In long-standing cases, the mucosa can become
atrophic with lymphoid aggregates, some with
germinal centers. These lymphoid aggregates
represent an induced form of mucosa associated
lymphoid tissue, or MALT, which can transform into
lymphoma.
Diagnostic Tests for H. pylori
 Demonstration of H. pylori in tissue (remains the gold
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standard for detection of H. pyori)
Serologic test for antibodies to H. pylori
Fecal bacterial detection
Urea breath test based on the generation of ammonia by
the bacterial urease
Gastric biopsy specimens: Histological examination
(refer special stains mentioned above), analysis by the
rapid urease test, bacterial culture, or bacterial DNA
detection by PCR.
Peptic ulcer disease is a complication of chronic H. pylori
gastritis.
Demonstration of H. pylori:
 Initially H. pylori gastritis is limited to gastric antrum and
later may extend to involve the body and fundus.
 H. pylori are concentrated within the superficial mucus
covering the epithelial cells in the surface and neck regions.
 H. pylori have an affinity for gastric epithelium and are
generally not found in association with intestinal metaplasia
or duodenal epithelium.
 Special stains for H. pylori: Organisms can be easily
demonstrated with special stains.
 – Modified Giemsa stain and Diff-Quik are popular,
quick, cheap, and easy to perform.
 – Silver stains: Warthin-Starry, Genta stain.
 – Immunohistochemistry for Helicobacter.