acid secretion

7/29/2019 Acid Secretion

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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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acid secretion

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