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Causes, mechanisms and consequences of acute and chronic gastritis.

Explain the causes, mechanisms and consequences of the failure of the defences
of the stomach against injury by acid and pepsin acutely.
Regulation of acid secretions.
Regulation of acid secretion is a combination of neural, endocrine
and paracrine control.
Potentiation occurs where the effect of a combination of
stimulants is greater than the sum of the individual responses.
Stimulation of
Description:
parietal cells
secretion by:
Acetylcholine
Ach is released from the vagus nerve acting
(Ach).
through muscarinic M3 receptors.
Gastrin.
Gastrin is released in blood from G cells in the
antrum, in response to acetylcholine.
Gastrin acts through the gastrincholecystokinin receptors on parietal cell.
Histamine.
It is released from enterochromaffin-like (ECL)
cells in the stomach body and acts through
histamine H2 receptors. Both gastrin and Ach
can stimulate histamine release.

Somatostatin, released from D cells is stimulated by acidic pH,


Ach and gastrin.
Somatostatin acts directly on parietal cells to inhibit acid
secretion, G cells to inhibit gastrin release and ECL cells to inhibit
histamine release.

Normal stomach defences against acid


The gastric mucosal barrier is composed of bicarbonate-rich
mucus gel layer. This creates a pH gradient such that near the
epithelium is pH 7
The negatively charged bicarbonate mucus layer is also
coated by a phospholipid layer. The hydrophilic heads of the
phospholipids bind to the mucus while the hydrophobic tails
points into the lumen, repelling fluid and H+ ions.
Tight junctions between epithelial cells prevent H+ leakage
across the epithelium.
Prostaglandins reverse mucosal injury by inhibiting acid
secretion, promote mucosal blood flow and promote
bicarbonate/mucus secretion
Breakdown of barrier
Causes of acute gastritis
o H. pylori:

o NSAIDs/aspirin
o Bile, alcohol, drugs (chemical injury)
o Stress (shock, burns, severe trauma)

o Head injuries
o Septicaemia,
staphylococcal food poisoning (due to

microcirculatory changes following shock/sepsis)


Mechanism:
o H. pylori - acute inflammatory response against bacteria
is mediated by IL-8 and soluble chemoattractants
o Stress ulcers - insufficient perfusion causes ischaemic
necrosis of gastric epithelium. These may be due to
hypovolaemia due to burns (Curling ulcers) or shock.
o Cushing ulcers - intracranial injuries stimulate vagus
nerve, overstimulating H+ secretion
o NSAID induced - blockade of prostaglandin synthesis at
cyclooxygenase blocks the normal prostaglandin-

mediated repair of stomach mucosa


Consequences
Erosion of mucosa (coagulative necrosis of epithelium and breach of mucosa
without involving submucosa)
Haemorrhage due to erosion into a blood vessel
Ulceration (penetration into submucosa)
Resolves in 24-48 h due to cell turnover
(H pylori) transient hypochlorohydria up to 4 mths after infection
H. pylori begins as acute infection, usually progresses to chronic in 3-4 weeks
or rarely spontaneously heals.
Explain the causes, mechanisms and consequences of the failure of the defences
of the stomach and duodenum against injury by acid and pepsin chronically.

Causes
o Autoimmune
o H. pylori
o Chemical
Mechanism
o Autoimmune - immune-mediated destruction of acid-secreting tubules
in corpus
o Chemical - reflux of duodenal alkali juices and bile; prolonged NSAID
use
Consequences
o Autoimmune
Achlorhydria (loss of acid production)
Pernicious anaemia (loss of intrinsic-factor production or
intrinsic-factor antibody binding to B12, leading to
malabsorption of vitamin B12)
Hypergastrinaemia (due to loss of feedback of H+ on D cells,
leading to lack of somatostatin production, causing lack of
inhibition of G cells)
Linear/nodular ECL hyperplasia (due to hypergastrinaemia
overstimulating ECLs), occasional carcinoidosis
Production of autoantibodies against parietal cell membrane
H+/K+ ATPase, intrinsic factor and gastrin receptor
o H. pylori
infiltration of chronic inflammatory cells
expression of non-curative antibodies
Loss of parietal cells due to atrophic pan-gastritis leads to loss
of acid production, predisposing to GIT infections (no acid to
kill other bacteria)
Loss of intrinsic factor production leads to B12 pernicious
anaemia
o (General)

Erosion into a blood vessel and continued bleeding may cause


rapid blood loss (leading to haematemesis or melaena) or iron
deficiency anaemia due to slow blood loss
Stenosis - scarring near the pyloric sphincter or lower
oesophageal sphincter interferes with normal function

Appreciate the morphologic features of Helicobacter gastritis and duodenitis and


the role of these conditions in the development of chronic peptic ulceration.
Pathogenic factors of H. pylori:
o Helicobacter pylori is motile because it has a flagella and it can move
down the mucous layer in corkscrew manner. It is capable of winding
itself through mucus gel layer.
o It colonises the neutral zone of the mucus barrier
o It has urease, turning urea into ammonia (basic) and CO2
o It can survive in low oxygen tension
o They express adhesins, allowing them to attach to the epithelium
Antrum -dominant gastritis
o Antrum-dominant gastritis is characterised by increased acid
production (due to destruction of D cells).
o This increased acid production stresses the duodenal epithelium,
causing it to undergo gastric metaplasia (resembles gastric epithelium).
o H. pylori can now colonise the duodenum (since it has gastric
epithelium)
o This predisposes to duodenal ulcers
Pan-gastritis
o Gastric ulcers are due to the breakdown of mucosal defences in the
body of the stomach.
o Atrophy and intestinal metaplasia may also occur in the body, leading
to the metaplasia-dysplasia-carcinoma sequence or MALT lymphomas
Appreciate the long-term consequences of Helicobacter infection including the
metaplasia-dysplasia-carcinoma sequence.

After development of chronic and atrophic gastritis due to H. pylori,


epithelium may begin to be replaced by intestinal goblet cells (intestinal
metaplasia). These cells eventually become dysplastic (loss of differentiation).
Continued genetic lesions lead to adenocarcinoma (gastric cancer).
Chronic inflammatory cells may aggregate in the stomach mucosa to form
mucosa-associated lymphoid tissue (MALT)
o Mutations of the lymphocytes of MALT can lead to lymphomas (e.g. B
cell 'marginal zone' lymphoma). These can invade gastric pits and
metastasise

Explain the process of inflammation and healing in acute and chronic peptic
ulcers.
Damaged barrier allows H+ to leak back across the epithelium into the lamina
propria

H+ stimulates mast cells to release histamine and other inflammatory


mediators (which cause vasodilation, exudation, loss of fluid and blood into
the stomach lumen)

Explain the terms erosion, ulceration, penetration and perforation.

Erosion - breach in mucosa without penetrating through muscularis mucosa


Ulceration - penetrates through muscularis mucosa into submucosa
Chronic ulceration - all layers penetrated underlay by dense fibrosis.
Perforation - in anteriorly located ulcers, the ulcer may go through the entire
wall into the abdominal cavity. This leads to generalised peritonitis.
Penetration - ulcer goes through wall into an adjacent organ (e.g. liver,
pancreas, colon)

smoothed stomach mucosa, small pinpoint haemorrhages

RHS - coagulative necrosis of the epithelium. Very few inflammatory


cells

Superficial accumulation of
inflammatory cells

Mucosal breach without penetration through muscularis mucosa

Duodenum can also


erode due to acid from stomach. Intestinal metaplasia (replacement
of gastric epithelium with goblet cells) in the top right.

Breach into
submucosa.

Top left - replacement of parietal cells by pyloric-type cells and


elongated gastric pits. Mucosa is thinned and has a chronic
inflammatory cell infiltrate

Margins are neatly punched out. Mucosal fold radiation is due to


fibrosis and contraction of myofibroblasts dragging folds towards
ulcer.
By contrast, gastric cancers often do NOT have the folds continuing
to the ulcer margin - instead they have a smooth surface
surrounding the ulcer.
Two types of gastric cancer:
Intestinal type adenocarcinoma - glandular/tubular
morphology
Linitis plastica (diffuse type carcinoma) - all mucosal folds
flattened, stomach shrunken and wall thickened. Histologically
characterised by signet ring cells - dyscohesive single cells
filled with mucin

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