Pathophysiology of Peptic Ulceration Gastric Acid Secretion Gastric Mucosal Barrier Pathogenesis of Peptic Ulceration 27-Apr-17 gastric secretion

Gastric Secretion Gastric juice HCl Electrolytes Mucus, Water Intrinsic factor Bicarbonate 27-Apr-17 gastric secretion

Gastric Gland Gastric (oxyntic) gland Gastric lumen Gastric (oxyntic) gland Surface epithelia cells (mucus cells) Alkaline mucus- viscid Mucous neck cells (neck chief cells) Soluble mucus pepsinogen Columnar mucus cells Mucous neck cell Parietal cell Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

Gastric Gland Parietal cells (oxyntic cells) Hydrochloric acid Gastric lumen Parietal cells (oxyntic cells) Hydrochloric acid Intrinsic factor Chief [peptic] cells (zymogen cells) Pepsinogen Columnar mucus cells Mucous neck cell Parietal cell Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

Gastric Gland Enterochromaffin cells Specialized cells serotonin Gastric lumen Enterochromaffin cells serotonin Histamine Specialized cells vasoactive intestinal peptide (VIP) Substance P Glucagon Columnar mucus cells Mucous neck cell Parietal cell Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

Gastric Gland Parietal cell Produce a solution containing Gastric lumen Parietal cell Produce a solution containing Approx. 160 mmol of HCl/l; pH 0.8 (H+ conc. = 3 to 4 million time that in plasma) Energy cost = 1500 calories/l of HCl Columnar mucus cells Mucous neck cell Parietal cell Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

Gastric Gland Parietal cell Gastric lumen Intrinsic factor (vit. B12 - R factor binding macromolecule) Parietal cell Also produce Gastric lipase Gastric amylase Gelatinase Columnar mucus cells Mucous neck cell Parietal cell Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

Gastric Gland Chief cells Gastric lumen Chief cells Produce small volume of electrolyte similar to ECF Contain Pepsinogen( PG I, PG II) Some individuals secrete ABO blood group antigen in their gastric juice Columnar mucus cells Mucous neck cell Parietal cell Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

Pyloric Gland Similar structure like the oxyntic gland Have G-cells Gastric lumen Similar structure like the oxyntic gland Contain few peptic (chief) cells No parietal cells Contain mucus cells Have G-cells Columnar mucus cells Mucous neck cell G-cells Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

Pyloric Gland secrete G cells produce Gastrin Gastric lumen secrete Mucus and electrolytes G cells produce Gastrin Peptic cells produce pepsinogen Columnar mucus cells Mucous neck cell G-cells Peptic cell From Physiology Book by H.T. Sherrief 27-Apr-17 gastric secretion

HCl Secretion Function of HCl Participates in the breakdown of proteins Provide optimal ph for pepsin Hinders growth of pathogenic bacteria 27-Apr-17 gastric secretion

Mechanisms of HCL Secretion Chloride ions are actively secreted into lumen of canaliculi Against concentration gradient creates a negative potential -40 to -70 mv in canaliculi passive diffusion of K+, Na+ KCl, NaCl 27-Apr-17 gastric secretion

Mechanism of Acid Secretion The H+ conc. In parietal cells 3 to 4 million fold higher than in blood Cl- is secreted against Concentration and electrical gradient Ability of parietal cell to secrete acid Dependent on active transport 27-Apr-17 gastric secretion

Mechanism of Acid Secretion Key player in acid secretion H+/K+ATPase or “proton pump” Mg++ dependent 27-Apr-17 gastric secretion

Mechanisms of Acid Secretion Dissociation of H2O H2O  H+ + OH - The H+ is then actively secreted into the lumen by active pump in exchange of K+ Proton pump H+/K+ ATPase 27-Apr-17 gastric secretion

Mechanism of Acid Secretion Na+ is actively reabsorbed by a separate pump Thus most of the Na+, K+ that had diffused into canaliculi Reabsorbed into the cell H+ take their place Giving strong soln of HCL 27-Apr-17 gastric secretion

Mechanism of Acid Secretion The OH - combine with CO2 to form HCO3- Carbonic Anhydrase The HCO3 - diffuses to ECF and into blood Alkaline tide 27-Apr-17 gastric secretion

Mechanism of Acid Secretion H2O passes through cell and into canaliculi by OSMOSIS Final secretion from the canaliculi contain HCL at a conc of 150 to 160 mEq/l KCl at conc of 15 mEq/l Small amount of NaCl 27-Apr-17 gastric secretion

CO2 CO2 H20 CO2 + OH- H+ HCO3- HCO3- K+ H+ K+ K+ K+ Na+ Na+ K+ K+ Na+ Cl- Cl- Cl- H20 H20 H20 27-Apr-17 gastric secretion

Pepsinogen Secretion Precursor of pepsin Produced by the Chief Cells Stored in secretory granules Vagal stimulation, Histamine, Gastrin Cause preformed granules to be released into lumen 27-Apr-17 gastric secretion

Intrinsic Factor Mucoprotein Essential for vitamin B12 absorption Secreted by parietal cells 27-Apr-17 gastric secretion

Control of Gastric Acid Secretion Basal secretion During fasting gastric juice secretion occurs Postprandial Cephalic, gastric and intestinal phases 27-Apr-17 gastric secretion

Cephalic Phase Before food gets into the stomach Sight , smell, thought, taste, hunger,appetite center Cause reflex stimulation of gastric secretion This phase of secretion Accounts for 20% of total gastric secretion associated with eating a meal 27-Apr-17 gastric secretion

Gastric Phase Presence of food in the stomach excite Stretch receptors, chemoreceptors Local enteric reflexes gastrin production All these lead to stimulation of gastric secretion Gastric phase of secretion Account for 70% of total gastric secretion associated with eating a meal 27-Apr-17 gastric secretion

Intestinal Phase Presence of food in the intestines Release of Gastrin by duodenum Continue to stimulate secretion of some gastric juice 27-Apr-17 gastric secretion

Control of Gastric Acid Secretion Neural mechanisms Stimulation of vagus Stimulates intramural plexuses Which then stimulates PARIETAL, CHIEF, MUCUS cells Neurotransmitter is Acetylcholine 27-Apr-17 gastric secretion

Control of Gastric Acid Secretion Vagal stimulation increases secretion by Stimulating histamine releasing cells Histamine then diffuses to stimulate parietal cells Vagal stimulation activates antral G – cells Produce Gastrin Gastrin acts on parietal and chief cells 27-Apr-17 gastric secretion

Control of Gastric Acid Secretion Humoral Gastrin Secreted by G - cells Peptide G34, G17 G17 more abundant and potent than G34 for acid secretion 27-Apr-17 gastric secretion

Control of Gastric Stimulation Stimulus for Gastrin secretion Vagus Secretagougues (AA,peptides, alcohol,caffeine,Ca++ Distension of stomach Gastrin release intracellular Ca++ promote proton pump Cl- channel insertion 27-Apr-17 gastric secretion

Control of Gastric Acid Secretion Histamine Enterochromaffin cells Mast cells Acts on H2 receptors Increases cAMP This then promote proton pump function increases H+ secretion 27-Apr-17 gastric secretion

Control of Gastric Acid Secretion H2 receptor blockers Cimetidine etc Prostaglandin E1, E2 inhibit histamine release Pentagastrin stimulates HCl and Gastrin release 27-Apr-17 gastric secretion

+ + - - + - + + Ach Gastrin Histamine Somatostatin ECL Cells D- Cells H2 receptor Histamine ATP - + Adenyl cyclase - D- Cells cAMP + Prot kinase K+ Somatostatin H+ G - Receptor  Ca++ Ach - Receptor + 27-Apr-17 gastric secretion

Inhibition of Gastric Juice Secretion Acidity of gastric juice to pH <3.0 Gastrin mechanism is blocked Enterogastric reflex Presence of food in SI Distension, acidity, FA, AA Secretin, cholecystokinin Oppose stimulatory effect of Gastrin 27-Apr-17 gastric secretion

Enterogastric Reflex CCK GIP gastric inhibitory peptide Initiates enterogastric reflex Slows gastric emptying Inhibit gastric secretion GIP gastric inhibitory peptide Inhibit Histamine VIP vasoactive Intestinal peptide; somatostatin Have moderate inhibitory effects on gastric secretion 27-Apr-17 gastric secretion

Gastric Mucosal Barrier Protect the gastric lining cells from Damage by intra-luminal HCL Autodigestion 27-Apr-17 gastric secretion

Gastric Mucosal Barrier Compact arrangement of epithelial cells with TIGHT JUNCTION Epithelial cells secrete bicarbonate (under influence of prostaglandin) Thick layer of adherent MUCUS (alkaline mucus) 1 mm thick 27-Apr-17 gastric secretion

Gastric Mucosal Barrier Regenerative capacity of mucosa Trophic effect of Gastrin High turn over rate: Entire mucosa replaced within 3 days 27-Apr-17 gastric secretion

Peptic Ulcer Peptic ulcer is a mucosal lesion of Gastric acid & pepsin Stomach (gastric ulcer) Or duodenum (duodenal ulcer) Gastric acid & pepsin Play major pathogenic role Helicobacter pylori infection Play a major role as well 27-Apr-17 gastric secretion

Peptic Ulcer 27-Apr-17 gastric secretion

Peptic Ulcer Peptic ulcer also include Gastric ulcers & duodenal ulcers associated with Stress Ingestion of drugs Aspirin, NSAIDS Gastrin producing tumours Zollinger – Ellison syndrome 27-Apr-17 gastric secretion

Peptic Ulcer Thought to result from imbalance between Aggressive factors Protective factors Aggressive factors Protective factors Gastric mucus, bicarbonate, prostaglandins, blood supply Acid & pepsin H. pylori, irritation, aspirin, NSAIDS 27-Apr-17 gastric secretion

Helicobacter Pylori Infection occurs in about 95% of patients with duodenal ulcers 75% to 85% of patients with gastric ulcers The infection is also found in 25% of people without peptic ulcers Thus other factors Must be present to trigger ulcer formation 27-Apr-17 gastric secretion

Helicobacter Pylori Spiral shaped bacillus Gram negative Acid Gastric lumen Spiral shaped bacillus Gram negative Penetrate mucus layer Adheres to luminal surface of gastric epithelial cells Does not invade the gastric mucosa pH2 mucus pH 7 H. Pylori Parietal cell 27-Apr-17 gastric secretion

Helicobacter Pylori Thrives in highly acid environment Produces urease enzyme For ammonia formation Neutralize the acid Produces a number of toxins Cause inflammation & damage to epithelium 27-Apr-17 gastric secretion

Helicobacter Pylori Produces proteases & phospholipases Degrade the glyco-lipid complex of mucus gel  The thickness of mucus gel 27-Apr-17 gastric secretion

Helicobacter Pylori Stimulate chronic gastritis associated with Depletion of somatostatin from d-cells Gastric release from G-cells Stimulate acid production 27-Apr-17 gastric secretion

Other Pathogenic Factors DU patients as a group Secrete more acids than normal individuals 27-Apr-17 gastric secretion

Other Pathogenic Factors Some DU patients have True G cell hyperplasia G cell hyperfunction or Increased sensitivity of parietal cells to stimulation Increased capacity to secrete acid and pepsin 27-Apr-17 gastric secretion

Other Pathogenic Factors However, some patients with DU secrete normal amount of acid. May be Secrete abnormal mucus Failure of protective barrier 27-Apr-17 gastric secretion

Other factors Gastric emptying Stress and DU Accelerated More acid is being delivered to duodenal bulb than in normal Stress and DU Emotions and anger increase GASTRIC ACID and PEPSIN secretion Smocking 27-Apr-17 gastric secretion

Other factors Renal failure Severe Burns Increased incidence of DU Have high level of circulating Gastrin Severe Burns Develop stress ulcers (curling Ulcers) ? Hypergastrinaemia 27-Apr-17 gastric secretion

Other Factors Zollinger – Ellison syndrome Excessive production of Gastrin from islet cell tumor (Gastrinoma) Hyper-secretion of gastric acid Rapid recurring ulceration despite therapy 27-Apr-17 gastric secretion

Physiological Basis of Treatment Helicobacter pylori eradication Successfully prevents relapses Eliminate need for The long term therapy 27-Apr-17 gastric secretion

Physiological Basis of Treatment Treatment regiment include Proton pump inhibitor Taken together with 2 antibiotics Amoxicillin + metronidazole 27-Apr-17 gastric secretion

Physiological Basis of Treatment Antacids Widely available for self medication Relief of minor dyspepsia Majority of drugs based on Combinations with Calcium, aluminium, magnesium salts 27-Apr-17 gastric secretion

Physiological Basis of Treatment However, have side effects Calcium compound Cause constipation Magnesium compounds Cause diarrhoea Aluminium compounds Block absorption of other drugs Digoxin, tetracycline 27-Apr-17 gastric secretion

Physiological Basis of Treatment Histamine – H2 receptor antagonists Competitive inhibition of histamine at H2 receptor on parietal cell Cimetidine, ranitidine 27-Apr-17 gastric secretion

Physiological Basis of Treatment Proton pump “H+/K+ ATPase” inhibitor Irreversible inhibition of “H+/K+ ATPase” pump in the parietal cell  Gastric acid production Most powerful inhibitor of Gastric acid secretion 27-Apr-17 gastric secretion

Achlorhydria and Hypo-secretion Hypo-secretion of gastric acid Usually when acid is not secreted pepsin is also not secreted Correlate with histological lesions and the extent of gastritis Gastric atrophy Complete failure of gastric secretion ACHLORHYDRIA 27-Apr-17 peptic ulcers

Type A Gastritis Associated with possible parietal cell antibodies Diffuse involvement of mucosa Little or no gastric acid secretion Familial occurrence Associated with pernicious anaemia Intrinsic factor 27-Apr-17 peptic ulcers

Type B Gastritis More common than type A Parietal cell antibodies are absent Gastric mucosa and antrum may be involved Acid secretion is only moderately impaired 27-Apr-17 peptic ulcers

Hypo-secretion Occurring as a result of gastritis or by use of H2 receptor blockers May lead to bacterial overgrowth Production of Nitrosamine Has been implicated in the pathogenesis of gastric cancer 27-Apr-17 peptic ulcers