Gastric Secretions Christine Waasdorp Hurtado, MD, MSCS, FAAP

Gastric Secretions Christine Waasdorp Hurtado, MD, MSCS, FAAP
University of Colorado School of Medicine Children’s Hospital Colorado Reviewed by Brent Polk, MD and Thomas Sferra, MD

NASPGHAN Physiology Education Series
Series Editors: Christine Waasdorp Hurtado, MD, MSCS, FAAP Daniel Kamin, MD This is a lecture series created by faculty from Children’s Hospital Colorado, Boston’s Children’s, Morgan Stanley Children’s Hospital of New York, and UCLA Children’s and supported by NASPGHAN. To maximize the effectiveness of the physiology series, the text document should be reviewed by lecture attendees before presentation of the PowerPoint. We encourage faculty and fellows to modify the content to meet their educational goals. Thanks to NASPGHAN for supporting this educational tool. Christine Waasdorp Hurtado, MD and Daniel Kamin, MD

Objectives Understand the stimuli responsible for the secretion of gastrointestinal hormones Understand the normal gastric secretory processes Know the functions of the gut-derived polypeptides Know the location of hormone-secreting cells in the gastrointestinal tract Understand the mechanism of action responsible for the physiologic effects of various gastrointestinal hormones Understand the process of intracellular hormone processing in the gastrointestinal tract Know how to evaluate gastric secretory processes The objectives are based on the core curriculum created by the ABP sub Board on Pediatric Gastroenterology.

Case #1 14 yo Mexican American male with 5-6 months of worsening epigastric abdominal pain. 2 days ago the pain worsened and he is now reporting black, tarry stools. HR 114 bpm, RR 35 bpm Abdomen is tender to palpation in the RUQ and epigastric areas. Bowel sounds are present. Discuss the differential diagnosis and the evaluation plan.

Case #1 KUB – Normal Hemoccult – Positive Stool cultures – Negative
EGD –Chronic antral gastritis with nodularity and duodenal ulcers visualized Biopsy – Lymphocyte and plasma cell infiltrate in lamina propria with lymphoid follicles. H. pylori organisms seen. Stool H. pylori - Positive

H. pylori H. pylori colonizes gastric epithelium of 50% of the world’s population. Complications include: Gastritis Peptic Ulcers Mucosa-associated lymphoid tissue lymphoma (MALT) Gastric cancer The organisms colonize gastric tissue. The organisms hydrolyzes urea locally increasing the pH. The flagella promotes motility in the mucus layer. The organism binds via adhesins to antigens on gastric epithelial cells, thus preventing mechanical clearance. Transmission is by person to person contact, although the mechanism is unclear (gastric-oral, fecal-oral, oral-oral). Infections in infants are very rare, even if the mother is infected. Re-infection rates are low, but recrudescence (same strain in <12 months) is common. Re-infection is estimated at 2% per person per year. The host immune response is responsible for the majority of the damage. GI manifestations include; gastritis, duodenal and gastric ulcers, GERD, gastric cancer and MALT. Extraintestinal manifestations include iron deficiency anemia, short stature and possible a role in ITP and other autoimmune disease. Image from:

H. pylori Acute infection causes hypochlorhydria
Mechanism for inhibition of acid secretion Pro-inflammatory cytokine interleukin-1β Suppression of proton pump α-subunit promoter activity Interference in trafficking via tubulovessicles Acute infection is associated with a transient hypochlorhydria. Several possible mechanisms are proposed for decrease in acid secretion early in infection. Image from: Science Photo Library

H. pylori Chronic infection Hypochlorhydria vs hyperchlorhydria
Antral vs Pangastric involvement The level of acid secretion depends on the severity and distribution of gastritis. Most patients have a pangastritis and produce less than normal acid. These patients will have gastric atrophy, increasing the risk for gastric ulceration and gastric adenocarcinoma. Antral predominant infections result in increased gastrin levels resulting in an increased number of parietal cells and therefore more acid production. 12% of infected individuals have an antral dominant infection. There is increased acid secretion due to reduced amounts of Somatostatin and increased gastrin. These patients are predisposed to develop a duodenal ulcer. Eradication of the organisms results in normalization of acid, gastrin and Somatostatin secretion.

Stomach The stomach is divided into 3 areas Stomach Function
fundus, corpus (body), and antrum Stomach Function Food and liquid storage Food digestion Delivery of partially digested food to the small intestine Image from:

Stomach Epithelium Epithelium has glands 2 gland types
Oxyntic gland = Parietal cell Body and Fundus (80% of stomach) Pyloric gland = G cell Antrum (20% of stomach) Stomach has 1 x 109 parietal cells and 9 x 106 gastrin cells. Image from: Kelley Capocelli, MD at Children’s Hospital Colorado

Oxyntic gland (stomach body and fundus)
Parietal cells: secrete acid Mucous cells: produce mucus and bicarbonate Enterochromaffin-like cells (ECLs): secrete histamine Chief cells: secrete pepsinogen and gastric lipase D cells: secrete Somatostatin (paracrine control of parietal and G cells) Parietal cells secrete HCl, transform growth factor-alpha, amphiregulin, and heparin-binding epidermal growth factor-like growth factor. EC cells have large amounts of serotonin (5HT). Release is stimulated by gastrin. 5HT has effects on gastric motility and secretion. Enterochromaffin cells: Contain 5HT and ANP Make ghrelin and obestatin GASTROENTEROLOGY 2008;134:1842–1860

Pyloric Gland (antrum and pylorus)
Mucous cells: produce mucus and bicarbonate G cells: neuroendocrine cells secrete gastrin Pyloric glands are branched and coiled at basal ends with longer pits. Pyloric gland cells turn over faster than the Oxyntic. EC cells have both 5HT and ANP. 5HT affects motility. Atrial natriuretic peptide (ANP) released from enterochromaffin cells helps regulate antral somatostatin secretion, but the mechanisms regulating ANP secretion are not known. In the antrum (pyloric mucosa), ACh neurons stimulate gastrin secretion indirectly by inhibiting SST secretion, the latter by a direct effect on the D cell and an indirect effect mediated by inhibition of atrial natriuretic peptide (ANP) secretion from EC cells. PACAP neurons stimulate SST, via release of ANP, and thus also inhibit gastrin secretion. It has also been reported that PACAP increases histamine release. Ach decreases EC release of ANP and therefore decrease D cell stimulation resulting in lower SST and increased acid secretion. In the antrum, dual paracrine pathways link SST-containing D cells to gastrin cells and to EC cells. D cells: secrete Somatostatin (paracrine control of parietal and G cells) Enterochromaffin (neuroendocrine) cells: Secrete ANP, 5HT Make ghrelin and obestatin GASTROENTEROLOGY 2008;134:1842–1860

Gastric Secretions The stomach secretes: Acid Water Electrolytes
Glycoproteins Mucin Intrinsic Factor Enzymes

Gastric Acid Gastric acid is necessary for:
Protein digestion Absorption of Ca+, iron, Vitamin B12 and thyroxin Prevention of bacterial overgrowth and enteric infections Reduction or elimination of food allergenicity(?) Gastric acid in excess results in ulceration A Swedish population study reported a possible correlation between recent food allergy increases and maternal acid suppression. Further studies are needed to prove causation.

Parietal cell acid secretion
The parietal cells, located in the body and fundus, generate acid. In the resting state the parietal cell is filled with vessicles. During acid secretion there are morphological changes to parietal cells: Translocation of cytoplasmic tubovessicles to the apical membrane with formation of secretory canaliculi Proton pump inserts into the apical canalicular membrane and starts transport of protons out of the cell in exchange for potassium. The activation of the parietal cell involves increases in cytoplasmic calcium followed by activation of a cAMP-dependent kinase cascade that results in movement of the proton pump to the apical surface. The proton pump, H+/K-ATPase , actively pumps H+ ions in exchange for K+. Parietal cell mitochondria provide the ATP for ATP hydrolysis provides the necessary energy for the membrane embedded proton pump. Cessation of acid secretion is associated with the re-internalization of the H+/K-ATPase pumps. The protons are created following parietal cell stimulation when water and acid enter the cell and combine under the influence of carbonic anhydrase to form carbonic acid (H2CO3) and subsequently HCO3- and H+ . The free H+ ions are excreted on the apical side of the cell in exchange for potassium. Bicarbonate ions are secreted on the basal side of the parietal cell in exchange for chloride. The HCO3- secretion results in an alkaline tide, which brings bicarbonate to the surface for secretion by gastric mucous secreting cells. Cl- is extruded down electrochemical gradient through channels using a cAMP pump in the apical membrane to help drive the Cl-/HCO3- exchange. H+/K-ATPase continues to exchange protons for K+ resulting in gastric acidification. Parietal cells secrete HCl at a concentration of 160mM or at about a pH of The median pH of the human stomach is Newborns have a gastric pH of 6.0 to 8.0 followed by a burst of acid secretion in the 1st or 2nd day of life which drops off again and reaches adult levels by 2 years of age. The average adult secretes 2-3 liters of acid rich fluid on a daily basis.

Control of Acid Secretion
Balance of Neural, Hormonal and Paracrine pathways Activated directly by stimuli from brain Reflex activation by stimuli in stomach and intestines Distension Protein/Lipid Acid

Mechanisms of Acid Secretion Control
Hormone Released into blood Reach targets via bloodstream i.e. - Gastrin Paracrine Released into tissue Reach targets by diffusion i.e. - Histamine and Somatostatin

Mechanisms of Acid Secretion Control
Neurocrine Released from nerve terminals Reach targets by synaptic diffusion i.e. - Acetylcholine and gastrin releasing peptide (GRP)

Stimulation of Acid Secretion
Three phases Cephalic Gastric Intestinal Physiologic stimulation is classically thought of in three phases: cephalic, gastric and intestinal.

Cephalic Phase Dorsal vagal complex + - ENS - - + FOOD IS COMING
Parietal cell ACh ACh + -  ENS   - - + ECL Histamine D cell (Somatostatin) The cephalic phase is responsible for 1/3 to 1/2 of gastric acid secretion. Activated by thought, taste, smell and sight of food, as well as swallowing. Mediated mainly by cholinergic and vagal mechanisms. Afferent from vagus nerve to brainstem (sensory information Efferent output via the vagal nerve (motor limb of vagovagal reflex) Vagal Stimulation via: Bombesin = Gastrin Releasing peptide (GRP) – Increases gastrin secretion Acetylcholine (ACh) – acts directly on parietal cells in body and fundus via M3 muscarinic receptors, which increase gastric acid secretion when stimulated. Inhibition via: 1. Somatostatin (SST) – Produced in D cells. Inhibits acid secretion with direct action on parietal cells and indirect action on ECL cells with a decrease in histamine secretion. SST also decreases gastrin secretion from G cells. FOOD IS COMING Smelling or thinking about food Pavlov’s experiments Slide from D Kamin, MD

Gastric Phase stretch + + ENS - + + Parietal cells G cells Chief cells
Dorsal vagal complex FOOD HAS JUST ARRIVED = beginning of gastric phase Stretch receptors via ENS Short and long reflexes Gastrin release ACh stretch + + ENS -  + + As food arrives in the stomach, the stomach expands and stimulates the stretch receptors. The stretch receptor stimulate release of gastrin via cholinergic activation. Gastrin then stimulates secretion of acid. The gastric phase is also stimulated by the chemical effects of food, such as the presence of amino acids. AA directly stimulate G cells, but there is additional cholinergic activation and GRP release due to presence of AAs in stomach. Gastrin is the major mediator of the gastric phase. The gastric phase results in a shift to activation of the parietal cells with increasing gastrin release and suppression of somatostatin. Parietal cells ACh or GRP G cells Chief cells Gastrin Gastrin Slide from D Kamin, MD

Gastric Phase Neutral pH stretch + ENS - + + Parietal cells G cells
Dorsal vagal complex FOOD IS HERE TO STAY Gastrin release continues D cells decrease secretion ACh Neutral pH stretch + ENS -  + Histamine + As food remains in the stomach the stretch receptors continue to be stimulated resulting in continued gastrin secretion. G cells are found deep in the antral gastric glands with innervation from vagus nerve. Gastrin-releasing peptides (GRP)(Also known as Bombesin) is released from vagal nerves, stimulating G cells to release gastrin. Amino acids in the stomach also stimulate G cells to release gastrin. Gastrin stimulates enterochromaffin-like cells to release Histamine. Parietal cells are stimulated by gastrin and by histamine to release HCl. D Cells provide some balance with the secretion of Somatostatin. Somatostatin inhibits parietal cells and G cells. D cells are activated by stimulation at the CCK receptors and by VIP secretion. The D cells are inhibited by acetylcholine stimulation of M3 receptors. D cells are important in the negative feedback mechanism when the pH is <3. Parietal cells G cells ACh or GRP D cells Gastrin Gastrin Slide from D Kamin, MD

Intestinal phase Somatostatin inhibition Gastrin and histamine
Decrease vagus stimulation Inhibit Gastrin release Dorsal vagal complex pH dropping  Gastrin - ENS   Intestinal phase plays a small role in stimulation of acid secretion. Somatostatin inhibition of Gastrin release Histamine release Directly on parietal cell Decrease vagus stimulation Return to basal acid secretion Likely intestinal endocrine factors inhibit Gastrin release Parietal cells - G cells Chief cells D cells pH sensor  Slide from D Kamin, MD

Hormonal Control of Acid Secretion
Gastrin Produced mainly by antral G cells Secretion stimulated by Gastric distention AA in lumen Stimulates gastric acid secretion during meal ingestion Direct stimulation of parietal cells via CCK-2 receptor Indirect stimulation of parietal cells via enterochromaffin-like cells (ECLs). Histamine released when stimulated by Gastrin Activates parietal cell H2 receptors Gastrin is the main hormone responsible for acid secretion. It is secreted mainly by antral G cells, but also in small amounts in non-antral stomach, duodenum, jejunum, ileum and pancreas. It is also found outside of the GI tract in the brain, adrenal glands, respiratory tract and reproductive organs, although the role in these tissues is unknown. Gastrin is released primarily in response to a meal. Proteins, peptides and amino acids in particular are responsible for gastrin release. The primary mechanism of action for acid release is by stimulating release of histamine from ECL’s. Gastrin activity is closely controlled by the release of gastrin-releasing peptide(bombesin) (stimulatory) and somatostatin (inhibitory). CCK-2 receptor is G-protein coupled receptor containing seven membrane-spanning segments with affinity for both gastrin and CCK. CCK-2 receptors have been located on parietal and ECL cells. ECL CCK-2 stimulation results in the release of histamine. Gastrin is synthesized via post-translational modification of preprogastrin by cleavage of a dibasic arginine residue by convertase. Circulating gastrin is a mixture of several peptides with 95% α-amidated. 90% of gastrin production is gastrin-17 and 10% is gastrin-34. Gastrin-17 is cleared 10x faster. This results in serum levels of gastrin-17 and gastrin-34 being similar. Gastrin also modulates acid secretion by it’s trophic effects on gastric oxyntic mucosa via: increases fibroblast growth factor, activation of epidermal growth factor receptors and mitogen-activated protein kinase.

Paracrine Control of Acid Secretion
Histamine Stimulates acid secretion Stored in ECLs in the basal half of the oxyntic gland Gastrin stimulates histamine release from ECLs Histamine binds to the H2 receptor on parietal cells leading to activation of proton pump. Secretion increased by gastrin, aspirin, indomethacin, dexamethasone, IL-1, and TNF Histamine is present in both mucosal mast cells and enterochromaffin-like (ECL) cells. Histamine is formed by decarboxylation of L-histadine by histadine decarboxylase. ECL cells are present in the oxyntic mucosa close to parietal cells. Gastrin is the primary trigger for histamine release from ECL cells. ECL cells are also stimulated by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). Histamine release is inhibited primarily by somatostatin, as well as calcitonin gene-related peptide (CGRP), peptide YY, prostaglandins and galanin. Gastrin stimulated ECLs degranulate, releasing histamine from the vessicles. Gastrin has not been shown to result in histamine release from gastric mast cells. Histamine is then the primary physiologic mediator of acid secretion. Stimulation of acid secretion is both direct and indirect. Direct stimulation by diffusion to parietal cells where H2 receptors are activated, generating cAMP. This is followed by translocation and activation of H+/K+-ATPase (proton pump). The indirect stimulation of acid secretion occurs by activating H3 receptors resulting in inhibition of Somatostatin.

Paracrine Control of Acid Secretion
Somatostatin Inhibits acid secretion Released from D cells Direct inhibition of parietal cells Indirect inhibition Decrease histamine secretion from ECLs Decrease gastrin secretion from G cells Released from D cells found throughout the gastric mucosa. Somatostatin’s primary effect is on the inhibition of histamine release from ECL cells, with lesser effects on gastrin release. Somatostatin also decreases acid secretion by direct inhibition of parietal cells. Somatostatin release is stimulated by gastric acid secretion and the presence of gastrin. It provides a vital negative feedback loop. Inhibitory effect of Somatostatin on gastrin secretion is mediated by Somatostatin subtype 2 receptor coupled to suppression of cAMP and to induction of menin. Somatostatin secretion is also affected by neural inputs, with suppression from cholinergic input and stimulation by VIP. Luminal acid activates sensory calcitonin gene-related peptide (CGRP) neurons. The activated neurons stimulate Somatostatin via an axon reflex. Somatostatin inhibits gastrin release. Gastrin also directly stimulates Somatostatin secretion and decreases further gastrin secretion. Decreases in luminal acid (gastric atrophy, antisecretory medications) result in a reduction of Somatostatin. The reduction of Somatostatin results in increased Gastrin. Hypergastrinemia induces ECL and parietal cell hyperplasia. Patients on prolonged PPI will have a rebound of acid secretion due to cellular hyperplasia from PPI use. Excess acid secretion reduces in 4-6 weeks.

Neural Control of Acid Secretion
Mucosal nerves respond to cephalic phase and to gastric distention and presence of AA. Bombesin (Gastrin Releasing Peptide) Increases Gastrin production Vasoactive intestinal peptide (VIP) Increased acid secretion due to ECL stimulation (transient) Decrease acid secretion via enhanced somatostatin release (sustained) Pituitary adenylate cyclase-activating polypeptide (PACAP) Stimulated EC cells to release ANP Increased histamine release Enteric nervous system (ENS) Intrinsic neurons Myenteric plexus (between circular and longitudinal muscles) Submucosal plexus (adjacent to mucosal layer) Extrinsic efferent and afferent neurons Vagus 80-90% afferent, 10-20% efferent Efferent fibers synapse with postganglionic neurons in ENS Postganglionic neurons contain -neurotransmitters including: Acetylcholine (ACh) Gastrin-releasing peptide (GRP) Vasoactive intestinal polypeptide (VIP) Nitric oxide Substance P PACAP

Neural Control of Acid Secretion
Acetylcholine release Increase acid secretion Stimulates Gastrin secretion Released from postganglionic nerves in Meissner’s plexus Binds to M3 muscarinic receptors on parietal cells Increase intracellular calcium Activate proton pump Inhibits somatostatin secretion by activation of M2 and M4 receptors on D cells Stimulates histamine release from ECLs by binding to to M1 receptor.

Summary of Parietal Cell Control
‘Inhibit the Inhibitors’ = a Stimulator! - D cell SST Rc cAMP - H3 + - M2 + + + ECL cells inhibit D cells, which inhibits SST release. D cells also have input from autonomic nervous system. In addition, Vagus outflow inhibits D cells. As Vagus outflow decreases, D cells are less inhibited and more able to inhibit acid secretion. ACh also stimulates acid secretion indirectly by activating both M2 and M4 receptors on D cells. This is coupled to inhibition of Somatostatin secretion, thus removing the tonic restraint exerted by this peptide on gastrin, ECL, and parietal cells. Stimulators Acetylcholine: neural control post-ganglionic via vagus Histamine: paracrine ECLs Gastrin: hormonal control 1o on parietal cell 2o on ECL via histamine D cell inhibition Decrease Somatostatin Inhibitors Somatostatin: paracrine On parietal cell On ECL cell On G cells Less Gastrin Less Ach via vagus This system has balance and redundancy that allows for exquisite control of acid secretion. Blocking one pathway doesn’t stop acid secretion, unless you block the proton pump. GASTROENTEROLOGY 2008;134:1842–1860

Prostaglandins Inhibit acid secretion
Receptors on parietal cells and gastric mucous cells Decrease histamine-stimulated parietal cell function Decrease gastrin stimulated histamine release Prostaglandins are product of macrophages and capillary endothelial cells Stimulate bicarbonate secretion

Other Regulators Transforming growth factor-alpha (TGF-alpha) in parietal cells Inhibits gastric acid secretion Peptide YY Released from ileum and colons cells post-prandially Inhibits gastric phase of acid secretion Binds to ECL cells, inhibiting gastrin stimulated histamine release

Inhibition of Acid Secretion
Carbohydrates in intestine decrease acid secretion – mechanism? Fat inhibits acid secretion CCK release Neural response activation

Gastrointestinal Hormones and Peptides
Leptin (Hormone) Produced by adipose tissue Present in fundic glands Pepsinogen granules of chief cells Inhibitory granules of endocrine-type cells Mobilized following food ingestion after a fast Role in satiety Ghrelin (Hormone) Increased secretion with fasting and inhibited by eating In gastric mucosal endocrine cells Stimulates gastric motility and gastric acid secretion Increase gastric emptying Also stimulates growth hormone and insulin secretion Ghrelin is a natural ligand for the growth hormone secretagogue receptor located in the oxyntic mucosa. Small amounts are present in the antrum, small intestine and colon. Levels increase before meals and decrease after meals. It is thought that Ghrelin triggers pre-meal hunger and promotes eating. Clinical correlation Suppressed following Roux-en-Y gastric bypass leading to weight loss. Stimulates gastric motility and acid secretion. Thought to increase acid secretion via vagal pathways and histamine release. Inhibited by both Somatostatin and H. pylori. The precise mechanisms of action are unclear.

Gastrointestinal Secretions
Orexin Increases food intake Bind and activate 2 G protein-coupled receptors Peripheral stimulation of gastric acid secretion Orexin-A and orexin-B are neuropeptides derived from propro-orexin by post-translational processing. They bind and activate two G protein-coupled receptors. Orexin and it’s receptors are present in the hypothalamus and gastric antrum.

Adrenomedullin (Peptide) Localized in ECLs in gastric fundus Stimulates gastric Somatostatin via neural pathways Inhibits histamine and gastric acid secretion Expression increases with gastric mucosal injury Peptide identifies originally in pheochromocytoma tissue. Recently identified in ECL cells in the gastric fundus. Adrenomedullin stimulates fundic somatostatin release via neural pathways. The somatostatin inhibits histamine and gastric acid secretion. Clinical correlation Shown to be increased following mucosal injury. Proposed to play a role in mucosal defense and epithelial healing.

Enterogastrones Factors that inhibit acid secretion following arrival of nutrients in the intestine Include: CCK Secretin Neurotensin GLP-1 Glicentin Oxyntomodulin

Cholecystokinin (CCK) Decreases acid secretion Binding to CCKa receptors on gastric mucosal somatostatin cells Dominates secretory function Stimulates acid secretion Binding to CCKb receptors on parietal and ECL cells

Secretin Inhibits gastrin release Decrease gastric acid secretion Secretin containing cells mainly in small intestine Duodenal cells release secretin in response to detection of gastric acid in small intestine lumen Also released when bile salts and products of fat and protein digestion enter the small intestine Stimulates pancreatic exocrine secretion of water and bicarbonate

Enterogastrones Mechanisms
Neurotensin – released by cells in the ileum in response to intraluminal fat GLP-1, glicentin and oxyntomodulin are co-localized in L cells. L cells increase in density in the small intestine. Released due to presence of luminal lipids and carbohydrates. Excess secretion of GLP-1 contributes to hypoglycemia in patients with accelerated gastric emptying.

Acid Control Summary This model illustrates the neural, paracrine, and hormonal regulation of gastric acid secretion. Efferent vagal fibers synapse with intramural gastric cholinergic (ACh) and peptidergic (gastrin-releasing peptide [GRP], vasoactive intestinal peptide [VIP], and pituitary adenylate-cyclase activating peptide [PACAP]) neurons. In the fundus (oxyntic mucosa), ACh neurons stimulate acid secretion directly via M3 receptors on the parietal cell and indirectly by inhibiting Somatostatin (SST) secretion, thus eliminating its restraint on parietal cells and histamine-containing enterochromaffin like (ECL) cells. Dual paracrine pathways link SST-containing D cells to parietal cells and to ECL cells in the fundus. Histamine released from ECL cells acts via H3 receptors to inhibit SST secretion. This serves to accentuate the decrease in SST secretion induced by cholinergic stimuli and thus augments acid secretion. In the antrum (pyloric mucosa), ACh neurons stimulate gastrin secretion directly and indirectly by inhibiting SST secretion, the latter by a direct effect on the D cell and an indirect effect mediated by inhibition of atrial natriuretic peptide (ANP) secretion from enterochromaffin (EC) cells. GRP neurons, activated by intraluminal protein, also stimulate gastrin secretion. VIP neurons, activated by low-grade distension, stimulate SST and thus inhibit gastrin secretion. PACAP neurons stimulate SST, via release of ANP, and thus also inhibit gastrin secretion. In the antrum, dual paracrine pathways link SST-containing D cells to gastrin cells and to EC cells. Release of acid into the lumen of the stomach restores SST secretion in both the fundus and antrum; the latter is mediated via release of calcitonin gene-related peptide (CGRP) from extrinsic sensory neurons. Acute infection with H. Pylori also activates CGRP neurons to stimulate SST and thus inhibit gastrin secretion. In duodenal ulcer patients chronically infected with H. Pylori , the organism or cytokines released from the inflammatory infiltrate inhibit SST and thus stimulate gastrin (and acid) secretion. GASTROENTEROLOGY 2008;134:1842–1860 GASTROENTEROLOGY 2008;134:1842–1860

Acid Blocking Medicine
Acid blocking medication have several different targets. Only blockage of the proton pump can block acid secretion. Reference 1. Robinson M. Innovations in acid suppression therapy: review of the proton pump inhibitors rabeprazole and pantoprazole. Pract Gastroenterol 1999;23(August suppl):1-20. Image from: Pract Gastroenterol 1999

Histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) suppress gastric acid secretion via different actions on the parietal cell. H2RAs inhibit the binding of histamine to specific (histamine-2) receptors on the basolateral surface. Activation of these receptors by histamine stimulates the parietal cell to secrete acid, by triggering a sequence of intracellular events that lead to activation of an enzyme called hydrogen/potassium adenosine triphosphatase (H+,K+-ATPase ). H+,K+-ATPase is the final step in acid production and is also known as the proton pump. Blockage of H2RAs does not stop acid secretion, which can also be stimulated by Ach and Gastrin. Proton pump inhibitors (PPIs), H+,K+-ATPase inhibitors, cross the membrane of parietal cells and accumulate in the secretory canaliculus, where they bind to and inhibit active proton pumps. Inactivation of the proton pump also blocks the effects of histamine and other stimuli. Diagram adapted from Sanders SW: “Pathogenesis and treatment of acid peptic disorders: comparison of proton pump inhibitors with other antiulcer agents.” Clin Therapeutics, vol 18, pp Copyright 1996 by Excerpta Medica Inc. Image from: Pract Gastroenterol 1999

Clinical Correlation Proton Pump Inhibitors Increased number of parietal cells Reduction of somatostatin levels Increased Gastrin. Hypergastrinemia induces ECL and parietal cell hyperplasia.

Clinical Correlation H2RA tolerance develops Patients on prolonged H2RA or PPI will have a rebound of acid secretion due to cellular hyperplasia from PPI use. Excess acid secretion reduces in 4-6 weeks. H2RA tolerance may begin as early as 7 days following start of therapy. No tolerance seen in PPI therapy. Rebound acid secretion is seen with both H2RA and PPI’s. Rebound can be seen as quickly as 25 days after therapy and typically stops after 9 days. More common in patients without H Pylori infection. Rebound can provoke symptoms. A double blind placebo controlled study with healthy volunteers found that 40% of subjects treated with PPI for 8 weeks had dyspepsia in the 4 weeks after cessation of therapy. Only 15% of placebo group experienced dyspepsia. Mechanisms of rebound - Hypertrophy of ECL cells due to elevated gastrin levels - Hypertrophy and hyperfunction of parietal cells due to elevated gastrin - Up regulation of histamine-independent stimulatory mechanisms mediated by vagal/cholinergic pathways - Down regulation of inhibitory pathways – i.e. - Somatostatin

Evaluation of Gastric Acid Secretion
NG sampling of gastric fluid (Gold Standard) pH Probe SmartPill 13C-labeled calcium carbonate breath test NG NG placed in dependent portion of the stomach with sampling of fluid. Gold standard for evaluation of gastric secretions. Complex evaluation. pH probe and Impedance Both pH studies have been used to assess gastric secretions. Clinically the most practical at the current time. Bravo probe is also used. SmartPill Records luminal pH, temperature and pressure during gastrointestinal transit. Breath test A novel 13C-labeled calcium carbonate breath test for the potential noninvasive measurement of stimulated gastric acid secretion. Ingested calcium carbonate is converted to calcium chloride, CO2, and water by HCl. The CO2 is rapidly absorbed by the gastric mucosa and delivered through the bloodstream to the lungs where it is excreted in the breath. Measurement of excess 13CO2 in the breath enables the amount of acid that has been secreted by the stomach to be calculated.

Gastric Mucus and Bicarbonate
Highly hydrated gel (95% H2O, 5% mucin and electrolytes) Mucus cells on luminal surface and down into the glands Protects epithelium Prostaglandins and secretin stimulate secretion of Bicarbonate

Gastric Enzymes Gastric Lipase Initiates digestion of fats
Hydrolyzes 20% of triglycerides Resistant to acid Secreted by fundic chief cells Detectable by 10 weeks of gestation Image from:

Gastric Enzymes Pepsinogen Secreted by gastric chief cells
Proenzyme converted to pepsin by gastric acid Necessary for protein digestion Stimulated by cephalic vagal input Secretion enhanced by: ACh CCK and gastrin Decreased secretions associated with anticholinergics, H2RAs, and vagotomy Present by gestation Pepsinogen secreting chief cells are present in oxyntic mucosa (Group I pepsinogens) and a different type is present on oxyntic and pyloric mucosa (Group II pepsinogens). Clinical Correlation Increased levels of Pepsinogen associated with duodenal ulcers and gastrinomas. Atrophic gastritis associated with low levels.

Pepsin Digestive enzyme necessary for protein digestion Mucolytic
Ulcerogenic Pepsin can autocatalyze pepsinogen to pepsin Pepsin inactive at pH >4

Gastric Peptides Intrinsic Factor (IF)
Parietal (body and fundus) cells secrete Binds Vitamin B12 1-5µg B12 absorbed daily (3-30µg in diet) Intrinsic Factor –Vitamin B12 complex Binds to Cubilin receptor in the ileal mucosa Absorbed by endocytosis In enterocytes, Cyanacobalamin transferred from IF to transcobalamin II Transports cyanacobalamin to plasma Cobalamin converted to active forms Methylcobalamin and 5-deoxyadenyosyl cobalamin Meat, liver, fish, eggs and milk are high in Vitamin B12 Dietary B12 is released from peptide and protein complexes in the stomach due to pepsin and acid. It then attaches to IF and a second B12 binding protein, R-binder. Clinical Correlation Autosomal recessive mutation, Imerslund-Graesbeck syndrome, of the cubulin receptor results in IF-Vit B12 malabsorption and megaloblastic anemia. Vitamin B12 deficiency can be caused by ileal resection, IF deficiency, bacterial overgrowth, pancreatic insufficiency or small intestinal disease. This results in megaloblastic anemia. Patients with hypochlorhydria due to acid blocking medications typically have enough IF to prevent Vitamin B12 deficiency.

Case #2 17 yo female with diabetes presents with several months of fatigue, recurrent candidiasis and worsening migraines Her evaluation has identified Megaloblastic anemia Negative screens for thyroid and celiac disease Image from: Wikipedia

Case #2 Physical exam EGD HR 110 bpm RR 30 Pale
Abdomen is soft with positive bowel sounds and she is non-tender with no masses EGD Thin rugae with no visible inflammation Biopsy with severe atrophic fundic gland gastritis. No visible parietal cells

Atrophic Gastritis Present in 2% of the population and 10% of patients with type I diabetes. Autoantibodies to parietal cells Achlorhydria due to absence of parietal cells Megaloblastic anemia due to vitamin B12 deficiency associated with loss of intrinsic factor Atrophic gastritis is a histologic diagnosis characterized with chronic inflammation, decreased glands and intestinal metaplasia. Chronic atrophic gastritis is limited to corpus-fundus mucosa and characterized by marked diffuse atrophy of parietal and chief cells. It can occur due to autoimmunity or chronic infection, such as H. pylori. Autoimmune gastritis is present in 2% of the population and 10% of patients with type I diabetes. Autoimmune atrophic gastritis is the most common cause of pernicious anemia in temperate climates. There is a 2.9 times increased risk of gastric adenocarcinoma. It is more frequent in individuals of Northern European and African American descent. Autoimmune gastritis is associated with serum anti-parietal and anti-intrinsic factor antibodies that result in deficiency of intrinsic factor (IF) and decreased availability of cobalamin (vitamin B-12). Pernicious anemia can occur due to low vitamin B-12. The clinical manifestations are related to deficiency in cobalamin, which causes severe gastric parietal cell atrophy. The disease has an insidious onset and slow progression. Cobalamin deficiency affects the hematological, GI, and neurologic systems. Constitutional: Pale , Tachycardic, Slightly icteric skin and eyes. Hematologic: Megaloblastic anemia GI: Sore tongue, Anorexia with weight loss, Diarrhea due to malabsorption associated with epithelium changes in the small intestine. Neurologic: These result from demyelination, followed by axonal degeneration and neuronal death. Symptoms include numbness, paresthesias, weakness, ataxia, and decreased mental function Diagnosis is by histology from multiple gastric sites. Support for the diagnosis with presence of anti-parietal and anti-IF antibodies in the serum. Vitamin B-12 levels are low (< 100 pg/mL). Gastrin levels will be elevated due to achlorhydria. In addition serum pepsinogen I levels are decreased and the ratio of pepsinogen I to pepsinogen II (< 20 ng/mL) has a sensitivity of approximately 96.2% and a specificity of 97% for detection of fundus atrophy. Treatment is removal of organisms, H. pylori, if present. If atrophy is from autoimmunity, supplementation with vitamin B12 is the therapy of choice at present.

Questions A 17 yo Mexican immigrant child has worsening abdominal pain over several months and develops black, tarry stools. She is seen and evaluated in the emergency department. A smart GI fellow is concerned about an acute H. Pylori infection. What is the most cost-effective test to confirm the diagnosis? Upper Endoscopy with Biopsy for Histology Upper Endoscopy with Biopsy for rapid urease test Serum H. Pylori IgG Stool H Pylori antigen Urea Breath test Answers: D. Stool antigen is the most cost effective test for diagnosis, but does not have the highest sensitivity or specificity of all the tests. B. Prolonged PPI use places patient at risk for acid hyper-secretion.

Review Question A patient has been taking a PPI for years and would like to stop therapy due to cost. You recommend they slowly wean off therapy to minimize what problem? Elevated serum histamine Acid hyper-secretion Development of gastritis Low serum gastrin Hypoglycemia What substance is most important to acid release? Histamine Gastrin Somatostatin CCK Answer A. Histamine is required for acid secretion and thus is the most important. Gastrin and Somatostatin both affect histamine levels, but are not directly responsible for acid release.

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Gastric Secretions Christine Waasdorp Hurtado, MD, MSCS, FAAP

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Gastric Secretions Christine Waasdorp Hurtado, MD, MSCS, FAAP

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