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Physiology of acid secretion
Prof. Emad M El-Omar
Department of Medicine & Therapeutics,
Aberdeen University, Aberdeen, Scotland
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Gastric acid secretion
Important non-immunological first line ofdefence against ingested bacteria
Ability to produce acid allowed vertebratesto ingest more complex diets but also
protected them against microbes that
gained access through the GI tract
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Important historical figures in the acid story
Pioneers: Beaumont, Prout, Pavlov, Edkins, Popielsky,Kowalewski, Kay
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Regulation of gastric acid secretion
Finely controlled process dependent on
overlapping neural, hormonal and paracrinepathways.
This ensures production of the optimal amount
of acid
Too little acid: problems with absorption of iron,
calcium, B12 and some drugs
Too much: oesophageal, gastric and duodenal
injury
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The gastric mucosal barrier:
why does the stomach not digest itself??
Surface mucous cells produce a thick alkaline-
rich layer of mucus Secretion of bicarbonate
High polarity of surface epithelial cells
Tight junctions between adjacent epithelial cells
Abundant blood flow
All these factors combine to produce andmaintain a protective blanket 200-300m thick
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Regulation of gastric acid secretion
The human stomach has an intricatesubmucosal plexus that secretes a variety oftransmitters including nitric oxide, vasoactiveintestinal peptide (VIP), gastrin releasing peptide(GRP), substance P & calcitonin gene-related
peptide (cGRP).
The gastric mucosa contains specialised cells
that secrete several important substancesincluding histamine, gastrin, somatostatin, HCl,pepsinogens, mucin, intrinsic factor, leptin andghrelin.
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Gastric gland
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Cell lineage
S. Karam et al
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Parietal cells
Binding of sercretagogues to parietal cells induces changes in
second messengers that regulate the translocation and activation ofthe H+/K+ATPase pump.
Upon stimulation of parietal cells, the pumps are translocated from
the cytoplasmic tubulovesicles into the membrane of the secretory
canaliculus, forming the microvilli lining the canalicular space
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H+/K+ATPase pump
Involved in the final stages of acid secretion.Stimulated by signals from H
2, muscarinic (M3)
and gastric receptors
Transports its cations as a cycle of
phosphorylation and dephosphorylation of thetransport protein
A KCl pathway is activated and the net result is
pumping of hydronium ions (H3O+
) at aconcentration of 160mM (pH 0.8), equivalent toa 4 million-fold gradient across the surface of the
parietal cell
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Cephalic phase
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Gastric phase
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Intestinal phase
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Control of acid secretion
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Helicobacter pyloriexerts a major
influence on the physiology of
gastric acid secretion
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H. pyloriin the stomach
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Effect ofH. pylorion basal gastrin levels
El-Omar et al Gastroenterology 1995
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Effect ofH. pylorion gastric acid secretion
El-Omar et al Gastroenterology 1995
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Amieva & El-Omar, Gastroenterology, in press
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Pathophysiology of duodenal ulcer disease
G
gastrin releaseCaused by somatostatinCagA+ve > CagA-ve
P
acid response to gastrinparietal cell massSensitivity unimpaired
because of absence of corpus
gastritis
duodenal acid loadDecreased HCO3-gastric metaplasiaHP colonisation
ulceration
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Eradication ofH. pyloriInfection
in DU Patients
CORPUS
Cure of gastritis
Reduction in acid
secretion
ANTRUM Cure of gastritis
Normalisation of gastrin &somatostatin
DUODENUM
Decreased acid
load & increased
bicarbonate
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Divergent Responses to H. pylo r iInfection
Chronic H. pyloriInfection
Mild Mixed
Gastritis
Normal Acid
No significant diseaseDU disease Gastric Ca
Antral predominant GastritisAcid, little or no atrophy
low risk of gastric ca
Corpus predominant Gastritis:Acid, gastric atrophy
high risk of gastric ca
? Bacterial ? Environment ? Host
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Gastric cancer
Global killer, 2ndcommonest cause ofcancer death
Retains a very poorprognosis in the West
Major advance in
understanding thepathogenesis camewith discovery ofH.
pyloriinfection
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Pathological evolution of gastric cancer:
Multi-stage process of carcinogenesisCorrea Model
Inflammation Loss of
parietal cells
Stem cell
amplification
Normal
mucosa
Chronic
gastritisAtrophic
gastritis
Intestinal
metaplasia
Gastric
dysplasia
Early stagesInflammation
Increased proliferation
increased apoptosis
AtrophyAchlorhydria
Bacterial overgrowth
Helicobacter pylor i
Late stagesAccumulation of
genetic changes
Loss of growth control
Decreased apoptosis
Invasion and metastasis
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The gastric cancer phenotype
Severe inflammation
corpus predominant pattern gastric atrophy
Hypo/achlorhydria Bacterial overgrowth
H pylori and risk of gastric cancer
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H. pyloriand risk of gastric cancer
Uemura et al N Engl J Med. 2001 Sep 13;345(11):784-9
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Effect of pH on intragastric bacteria
Intragastric pH1.5 Intragastric pH 7
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Amieva & El-Omar, Gastroenterology in press
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Candidate genes
Pro-inflammatory
Relevant to H. pyloriinfection Central role in gastric acid physiology
Polymorphic gene with functionallyrelevant genetic variants that are frequent
in the population
IL-1B (encoding IL-1)
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Interleukin-1 Beta
Important pro-inflammatory cytokine
Up-regulated by H. pyloriinfection
Most powerful gastric acid inhibitor known
Interleukin-1 cluster: IL-1B, and IL-1RN Gene polymorphisms:
IL-1B: C-T transitions at -511T+, -31C+
IL-1RN: penta-allelic 86 bp VNTR in intron 2 allele 2associated with inflammatory conditions
Role of composite pro-inflammatory
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Polymorphisms Non-cardia gastric cancer (N=188) Controls (N=210)N Odds ratio 95% CI n
0 22 1.0 (ref) 75
1 74 2.9 (1.6-5.1) 85
2 62 5.4 (2.7-10.6) 46
3-4 30 27.3 (7.4-99.8) 4
p p y
polymorphisms on risk of non-cardia gastric
cancer
Pro-inflammatory polymorphisms:IL-1B-31/-511*2,IL-1RN*2/*2
TNF-A-308*2,IL-10 ATA/ATAEl-Omar et al,Nature, 2000; El-Omar et al, Gastroenterology, 2003; 124: 1193-1201
HH++/K/K++ ATPATPase ILIL 11 t i itransgenic mice
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HH++/K/K++--ATPaseATPase--ILIL--11 transgenic micetransgenic mice
mHKATPmHKATP promoterpromoter hIL1RAhIL1RAsignal peptidesignal peptide
mature hIL1betamature hIL1beta
EcoRIEcoRI BamHIBamHI BamHIBamHI
hGHhGH intron/PAintron/PA
IL1B ELISA in gastric tissue ofHKATPase-IL1beta Tg mice (F1)
0
200
400
600
800
line F0
#19
line F0
#24
line F0
#31
line F0
#42
line F0
#40
WT
pg/m
l
Path findings:Large stomachs
Large spleens
Altered T and NK
cell numbers
HH++/K/K++--ATPaseATPase--ILIL--11 transgenic mice progress totransgenic mice progress to
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g p gg p gatrophy, severe dysplasia and canceratrophy, severe dysplasia and cancer
x 40x 40
x100x100
Courtesy of Dr Tim Wang
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H+/K+-ATPase-IL-1 transgenic mice Produce high IL-1 in gastric tissue
Achlorhydric Progress to atrophy, severe dysplasia and
cancer
Process accelerated by H. felis infection
First example of a single cytokine
transgenic gastric cancer model
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