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Lecture - H.

Pylori
Learning objectives
1. Describe the regulation of gastric secretion 2. Discuss the pathophysiology of peptic ulcer disease and the role of H. pylori 3. Discuss the pharmacological basis for the treatment of peptic ulcer disease and H. pylori 1. Discuss the epidemiology of peptic ulcer disease

Regulation of acid secretion


Acid secretion is up-regulated by:
ACh (vagal stimulation) Gastrin (antral G-cells) Histamine (ECL cells)

Gastrin is released into circulation in response to:


stomach distension, vagal stimulation (GRP and ACh), the presence of partially digested proteins and amino acids

Gastrin stimulates the release of HCl from parietal cells both indirectly and directly

Actions of Gastrin
i. ii. Acts on parietal cells directly Promotes release of histamine from ECL cells
Binding to CCKB receptors on both

Translocation of tubulovesicles containing H+/K+ ATPases into canalicular membrane

iii. iv.

Causes chief cells to secrete pepsinogen Promotes stomach contraction and relaxation of pyloric sphincter

Inhibition of gastrin secretion


Gastrin secretion is inhibited by:
Somatostatin (d-cells) Secretin (S-cells) Increased gastric acidity (by negative feedback)

Somatostatin is released from D cells in the gastric antrum in response to increased gastric acidity and suppresses release of gastrin
Increased acidity also reduces secretion of gastrin by negative feedback

Epidemiology of H. pylori and peptic ulcer disease


Helicobacter pylori epidemiology Prevalence increases with age Infection is more common in the developing world Increased prevalence in lower socio-economic status Oral-oral or faecal-oral transmission Peptic ulcer disease epidemiology Affect 10-15% of adult population Duodenal ulcer 2-3 times more common than gastric ulcer More common in elderly

Pathophysiology of peptic ulcer disease

H pylori increases GRP stimulated gastrin release


Colonizes gastric epithelium and increases local pH via urease enzymes
Provokes local inflammatory response and chronic gastritis Results in increased parietal cell mass and exaggerated acid secretion

Causes antral gastritis


Results in depletion of somatostatin from d cells Increased gastrin release
Hypergastrinaemia results in excess acid secretion

These effects may be potentiated by environmental factors e.g. smoking some remain asymptomatic

H. pylori colonizes gastric-type epithelium only


increased acidic load entering the proximal duodenum induces gastric metaplasia Bacterium is able to colonize small patches of duodenum Results in ulceration

Structure of a peptic ulcer

Treatment of H. pylori infection


Triple therapy regimes provide higher eradication rates resulting in long-term ulcer remission
First-line Omeprazole Metronidazole Amoxycillin Second-line Omeprazole Clarithromycin Amoxycillin If allergic to penicillin Omeprazole Metronidazole Clarithromycin

Gastric cancer
Presents with anorexia, weight loss, anaemia Usually incurable

Vast majority >95% attributable to H.pylori Small minority occurring in subjects never infected due to strong genetic predisposition
E.g. autosomal dominant E-Cadherin germline mutation

Outcome of H.pylori infection


>50% of general populatinn have H.pylori
>80% no associated disease 5-15% peptic ulcer disease 1-3% gastric cancer

H.pylori is a necessary but not sufficient factor for noncardia gastric cancer

H.Pylori and risk of Gastric cancer


Those with H.pylori who develop peptic ulcer disease are somehow protected from developing gastric cancer

Different outcomes of H.pylori

What determines progression to atrophic gastritis and gastric cancer?

Development of gastric cancer

Reversible stage and age of noncardia cancer progress

Screening of H.pylori
Very complex question Intervention studies not yet shown benefit in reducing cancer incidence All studies so far based on assumptions therefore results uncertain Less controversial Non-invasive H.pylori test and treating dyspeptics Reduce H.pylori prevalence by improving living conditions

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