Helicobacter Pylori, Gastritis and Peptic ulcer disease

Physiology
Gastric cellular anatomy:

The gastric epithelial cells are disposed in glands.

Different types of cells exist in different gastric regions.
In the gastric cardia, glands contain mainly mucinous and endocrine cells.
Oxyntic glands are located in the corpus and contain mucinous, parietal, chief, endocrine
and enterochrommaffine like cells (ECL).
The antral region contains pyloric glands with mucous cells and other endocrine Cells (G
cells, D cells).
Parietal cell is responsible for acid secretion and intrinsec factor secretion; chief cell secretes
pepsinogene that is cleaved by acid to pepsine (which is a proteolytic enzyme).
Mucous cell secretes mucus and bicarbonate.
Endocrine cell secretes: gastrine (G cell) somatostatine (D cell) and ECL secretes histamin.
The interaction between these cells and hormones is under a neural control and produces
acid secretion.

Gastric secretion:
The gastric secretion occurs in basal and stimulated conditions. The basal secretion responds to
vagal innervation and histamine and follows a circadian cycle with maximum during the night
and minimum level in the morning. The stimulated secretion occurs in 3 phases:
1. Cephalic phase: sight, smell and taste stimulate acid via the vagal nerve.
2. Gastric phase: nutrients (proteins) and distention of stomach stimulates gastrin release
from G cells that acts on the parietal cell.
3. Intestinal phase: nutrients and H+ entering the duodenum stimulates secretion of CCK
and secretin that inhibit acid secretion.
Gastric mucosal defense:
Gastric mucosa defend itself from H+, pepsin and other aggressive substances by a defense
system the gastric mucosal barrier working at 3 levels: Preepithelial, epithelial and post
epithelial.

Preepithelial: the mucus bicarbonate layer: mucine secreted by mucous cells form a gel that
limits back diffusion of H+, the bicarbonate serve to increase PH from lumen to the apical
cell membrane and buffers H+

Epithelial: the epithelial cells along with the tight junction between cells form a mechanical
barrier. The integrity and renewal of epithelial cells is assured by postglandines (PG)
epidermal growth factor (EGF).

Post epithelial: the vascular bed were the blood supplies Bic, nutrients, for cells to secrete of
mucous, and cell for renewel.
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Helicobacter Pylori and its effect on gastric secretion and gastric histology:
H. Pylori:
Gram-negative microaerophilic bacillus living between the mucous gel and the cell lining of the
stomach, without invading the cells, it is S shaped and has multiple flagella. It is responsible for
chronic gastritis, peptic ulcer disease, adenocarcinoma and malt lymphoma of the stomach.
To survive the acidic environnement it possesses a very active enzyme urease that converts
urea to NH3 and transforms its surround milieu into alkali niche (PH>4).
Other enzymes contribute to its ability to colonize the stomach (catalase, lipase, adhesins,
platelet activating factor); the virulent strains possess CAG-A (cytotoxin associated gene A),
VAC-A (vacuolating Cytotoxine A) and other cytokines that enables the bacteria to cause
mucosal damage, ulcers and cancer.
The bacteria survive only between PH4 and PH8 but can divides and grows between PH6 and
PH8. So even at the gastric PH of <2 H.Pylori creates around it a milieu of PH>4

Epidemiology of H.Pylori:
The prevalence and transmission of the bacteria is directly related to poor Socioeconomic status.
The prevalence is > 80% in developing countries, all ages considered. But in developed
countries the prevalence increases with age being <10% under 30 years and > 50% over 50
years. Transmission is by oro-oral and oro-fecal routes and occurred at infancy, the age
prevalence is therefore explained by the cohort phenomenon.

Pathophysiology:
The final effect of H.Pylori on gastroduodenal mucosa is an inter action between, bacterial
factors and host factors.
Bacterial factors:
Several proteins are implicated in mucosal damage:
Urease produces NH3 that alkalinizes the milieu, and is cytotoxic to the epithelial
cell.
Adhesins enable attachment of H.Pylori to the cells; this allows the cytokines of the
bacteria to act immediately on the cell.
CAGA pathogenicity island is a group of enzyme (CAGA, CAGB, Pic A, Pic B) that
induces cytotoxines and produces mucusal inflammation.
VAC-A produces vacuolar degeneration of gastric cells and ulcerations.
LPS: lipopaly saccharids of bacterial membranes are immunogenic by molecular
mimicry; this induces inflammatory response from the mucusal inflammatory cells
toward the bacteria.

Host factors:
All the virulent factors of the bacteria provoke inflammatory response by the mucosal cells, and
this produce the mucosal damage:

Epithelial cells and macrophages respond by secreting TNF (tumor necrosis factor alpha),
PAF (platelet activating factor) and interleukine 8,6.
These will act by recruiting neutrophils that secrete oxygen free radicals.
The end point of all these abnormalities is inflammation, necrosis and ulceration of the
mucusa.

Physiology of acid secretion: (Reminder)

Acid production by the parietal cell is stimulated: by vagal nerve and its acetylcholine:
o Directly by acting on M3 receptor of the parietal cell.
o Indirectly by stimulating the enterochromaffine like cell that releases histamine
that acts on H2R of parietal cell, and the G cell that releases gastrine that acts
directly on the G receptor of the parietal cell.
Acid inhibition is handled by the D cell that releases, under the adrenergic nerves and the
acidification of the milieu, the somatostatin, which inhibits gastrin release by the G cell.

H. Pylori and the stomach from colonization to disease

The acute phase:
H. Pylori induce acute inflammation with severe hyposecretion and achlorhydia. Two
mechanisms are possible:
1.

Over production of ammonia NH3 by urease. NH3 enters the epithelial cell followed by
calcium ions. The cell responds by secreting cytokine, (IL8), this induces attraction of
inflammatory cells: T lymphocytes, B-lymphocytes and macrophages, to produce
inflammation.

2.

Some peptides of H.Pylori are similar to the proton pump molecule of the parietal cell
(molecular mimicry). A vigorous antibody response from B-lymphocytes is directed
against the proton pump and inhibits its action: acid secretion is deeply inhibited.

This phase is transient (3 to 9 months), since the inflammatory reaction never succeeds to
eradicate H. P; a tolerant chronic phase follows for years with persistent infection and
inflammatory response. The acid secretion recovers.

The chronic phase:

The persistence of H. Pylori produces invariably chronic gastritis: Antral predominant, Corpus
predominant.

Antral predominant: if the host stomach hypersecretes acid before infection (like in
genetically increased parietal cell mass), H.P escapes the corpus rich in acid, and settles in
the antrum. It produces antral inflammation. Antral D cells are reduced by inflammation and
somatostatin secretion is decreased; this will lower the inhibitory drive on antral G cells. In
turn G cells secrete more gastrin so parietal cells respond by increase acid secretion.
Duodenum is overflowed by acid. The duodenal defense mechanisms are overwhelmed and
the intestinal duodenal epithelium is replaced by gastric metaplasia where H.Pylori can
migrate and induces duodenal inflammation and ulcerations.

Corpus predominant gastritis: if the host stomach secretes less acid (gene mutation produces
IL-1B with potent anti secretary effect), H. P colonizes the corpus and produces corpus
predominant or multifocal atrophic gastritis. The atroply interests all type of cells mainly
parietal cells and acidity is decreased. Atrophy reduces the cellular defense mechanisms
(less mucous gel, less PG production...) this provokes gastric ulcers. But more importantly,
atrophy is the bed for intestinal metaplasia, dysplasia and gastric adenocarcinoma.

Similarly, the chronic inflammation recruits inflammatory cell, T and B-lymphocytes. The
lymphocytes aggregate in follicles. At a certain moment gene mutations will produce a
monoclomal lymphocyte proliferation that evolves to MALT lymphoma.

Other pathophysiologic abnormalities in peptic ulcers

Duodenal ulcer: accelerated gastric emptying, decreased duodenal bicarbona
Gastric ulcer: delayed gastric emptying, duodeno gastric reflux of bile acid and pancreatic
enzymes
Elidemiology of peptic ulcer disease
H. Pylori is responsible for 90% of duodenal ulcers and 70% of gastric ulcers.
But only 10% of H.P infected individuals develop peptic ulcer.
In industrialized countries the rate of peptic ulcers is declining with the decline of H. Pylori
infection. But ulcers caused by NSAIDS are increasing.
Clinical features
Epigastric pain:
o Burning, gnawing, ill defined, or hunger pain.
o In DU patients, pain appears 2-3 hours after meal and is relieved by food and
antacids, awakes patient after midnight.
o In GU patients pain is increased by food.
o Sharp severe pain could be secondary to ulcer penetrating to the pancreas.
o The cause of pain is stimulation of chemical receptors in the mucosa by the acid.

Nausea and vomiting: if persistent think of duodenal obstruction.

Weight loss: possible but think of gastric cancer.
Hematemesis or melena think of bleeding ulcer.

Physical examination

Not specific epigastric tenderness.

But search for complications: peritonitis if perforation, orthostatic hypotension and
tachycardia if bleeding.

Complications of peptic ulcer disease

Gastro intestinal bleeding: in 20% bleeding is the presenting symptom. 15% of ulcer
patients bleed, mainly elderly people > 60 years, and NSAID users. Symptoms can be
hematemesis, melena or simply anemia by occult bleeding.

Perforation: 6-7% of cases. Perforation can cause generalized peritonitis with pain,
tenderness, ileus, abdominal rigidity. and free air under diaphragm on radiology studies.
Perforation can be confined to the pancreas (DU) with subsequent pancreatitis, or to the left
hepatic lobe (GU).

Gastric outlet obstruction: 1-2% of patients. Ulcer inflammation can distort the peripyloric
area limiting gastric emptying, causing early satiety, nausea vomiting and weight loss. It is
important to rule out gastric carcinoma. Medical treatment help to resolve inflammation but
when scarring and fibrosis, by old ulcers, appear treatment needs surgery or endoscopic
dilatation.

Differential diagnosis:

Non-ulcer dyspepsia: pain with no evidence of ulcer disease.

Gastro esophageal reflux disease.
Gastric or pancreatic tumors.
Pancreatitis.
Biliary colic.

Diagnosis
2 methods:

Barium studies: sensitivity is 90% but decreases in small ulcers (< 5 mm) and erosions.
DU shows crater in the bulb, GU presents as a crater with radiating folds when benign,
or with mass when malignant. This is not specific enough and endoscopy is required.

Endoscopy: the most sensitive and specific. Allows direct vision, detection of small
ulcers, biopsy to rule out malignancy, or other histological abnormalities and biopsy to
search for H.P.

Other ulcer diseases

A. NSAIDs induced ulcer

Non steroidal anti- inflammatory drugs.

Their anti inflammatory action is via the blockage of prostaglandin synthesis by

epithelial cells. PG have protective effect on the mucosa (part of the mucosal defense
barrier).
PG inhibitation induces at the mucosal level:
- Increased acid secretion.
- Decreased mucus synthesis and secretion.
- Decreased bic secretion.
- Decreased mucosal blood flow.
- Decreased epithelial cell proliferation.
At the level of the microcirculation PG inhibition induces:
- Increased adhesion molecule expression
- Neutrophil adherence

- Microvascular ischemia
- Release of oxygen free radicals
- Injury and ulcerations

NSAIDs have also a direct effect on the mucosa:

NSAIDs are acid molecules. In the acid milieu of the stomach they are absorbed by
the cell as non-ionized substance. Once in the neutral milieu of the cell they become
ionized, less lipophilic and less able to leave the epithelial cell (ion trapping), the cell
membrane is altered, facilitating H+ back diffusion and pepsin and subsequently
injury.

NSAIDs mucosal injury is independent of the presence of H.P but the bacteria can
adds its potential damage to the NSAID damage.

Epidemiology:

NSAIDs are the most commonly used drugs in the US.

70 million prescriptions a year.
Morbidity ranges from dyspepsia, nausea, to complications like bleeding and
perforation (4% users per year).
80% of the morbidity cases have no history of gastric disease.
It is important to identify NSAIDs users with high risk of complications in order to
protect them with concomitant use of anti ulcer drugs.

B. Stress related mucosal injury

In stress conditions: sepsis, shock, severe trauma and burns, head injury, multiples
erosions can develop with potential bleeding. This complication could be severe
enough to induce mortality in these fragile patients.
Ischemia by reduced mucosal blood flow and reduced mucosal protective barrier,
along with the gastric acid effect and H+ back diffusion are the mechanisms of the
mucosal injury.
Treatment consists in correction of shock, mucosal blood perfusion and increasing
gastric PH to > 3,5 by anti ulcer drug use.
C. Zollinger Ellisson syndrome
Definition:
ZES is a condition of unregulated gastrin hypersecretion from a gastrinoma with severe multiple
ulcers 90% and diarrhea 50%.
Less than 1% of PUD are due to gastrinoma which can be either sporadic or associated with
multiple endocrine neoplasia (MEN 1): pituitary, parathyroid, pancreas tumors.
Clinical features:
Ulcers are multiple, of different locations (oesophagus, distal duodenum) refractory
to medical therapy, relapsing and complicated with bleeding and perforation
Diarrhea, concomitant to ulcers or isolated. Its is due to acid volume increase,
inactivation of pancreatic enzymes and epithelial damage by acid, that interfere with
normal absorption.
Diagnosis
Fasting serum gastrin level > 150 pg / ml
Measuring acid production:
o Basal acid out put is increased > 15 meq / h
o Maximal acid out put after pentagastrin injection is not increased.
o BAO / MAO > 0,6
Stimulation tests:
o Secretine stimulation test: increases gastrin > 200 pg / ml, Sensivity is 90%
o Calcium stimulation test: increases gastrin > 400 pg / ml
o Standard meal test increases gastrin > 200% in case of G cell hyperplasia (an
entity that is due to H.P infection) and not ZES.
Tumor localization
Tumor is located in the duodenal wall in 50% of cases, and head of the pancreas.
Extra sites are possible: stomach, ovaries
Tumor is malignant in 60% of cases with liver metartasis in 30 50%
Different techniques are used to localize the tumor, with different sensitivities:
Ultrasound, CT scan, MRI, selective angiographic, octreoscan.
EUS is very sensitive to small tumors in the duodenal wall and pancreas.
Octreoscan is helpful in tumors with receptors to somatostatine, that uptakes this
radioactive somatostatine analogue.

Other types of Gastritis

The acute gastritis:

H. Pylori acute gastritis: pain, nausea and vomiting and hypochlorhydia.

Other bacterias or viruses: these are rare situations since acid milieu is not favorable. But in
immunocompromised patients some infection are possible: stepto, staphylococcus, E Coli
and viruses CMV, HSV.

The chronic gastritis:

Type A chronic gastritis:
Auto immune, associated with pernicious anemia (since the production of intrinsec factor
necessary to the absorption of vit B 12 is decreased).
Antibodies to parietal cells are present in 90% of patients: they are cytotoxic and directed
against the proton pump of the apical membrane. This will lead to mucosal atrophy and
decreased acid production. The increased Ph stimulates the antral G cells to produce more
gastrin, ( > 500 pg / ml ). The unopposed hypergastrinemia has a proliferative effect on
ECL cells (endocrine cells) that ultimately produces carcinoid tumors.
Type B gastritis: Bacterial = H. Pylori
o

Antral predominant.

Corpus or diffuse type with atrophy

Lymphocytic gastritis:
Infiltration of mucosa by T lymphocytes. Unknown etiology but may be associated with
coeliac sprue.
Eosinophilic gastritis:
Infiltration of the different layers by eosinophilis. Allergy can be the cause.
Granulomatous gastritis:
Crohn, tuberculosis. Sarcoidosis, syphilis, histoplasmosis
Menetrier disease:
Characterized by large tortuous gastric mucosal folds. This is due to massive foveolar
(glandular) hyperplasia with reduced density of chief and parietal cells.
Tumor growth factor may be responsible for these histologic findings.
Symptoms include pain, nausea, vomiting, weight loss, and bleeding.
Protein losing gastropathy can produce hypo albuminemia and edema.
The diagnosis is evoked by the findings of large folds and confirmed by endoscopic
biopsies.