Esophageal and Gastric Physiology

Richmond Sy, MD FRCPCDivision of GastroenterologyThe Ottawa HospitalSept. 8, 2015

Objectives Describe the mucosal protective mechanisms of the

esophagus and stomach.

Illustrate the role of the stomach in the digestion of food.

Explain the processes making up normal gastric secretion.

Summarize the regulatory mechanisms controlling gastric digestion, secretion and emptying.

Summarize the process of normal gastric contractility and emptying.

Gastric Anatomy

Functions of the Stomach Motor

Reservoir Mixing and grinding Controlled emptying

Secretory HCl secretion Mucosal barrier Pepsinogen secretion Intrinsic factor

Main function of Gastric Motility

Accommodate meal (receive food via receptive relaxation)

Grind down solids (triturate) to chyme Regulated emptying of stomach contents into the

duodenum The 3 major neuromuscular activities of the

stomach Receptive relaxation of the fundus Recurrent peristaltic waves of the corpus and

antrum Antral peristaltic waves coordinated with

antropyloroduodenal coordination

Gastric Electrophysiology Gastric pacemaker is located along the

greater curve at the proximal or mid corpus Gastric slow waves originate at the

interstitial cells of Cajal Slow waves propagate in longitudinal and

circumferential direction Migrate towards the pylorus at

14mm/second Coordinated propulsive peristaltic activity Do not go pass the pylorus

Fasting Stomach In fasted state, the motor activity of the stomach is

known as the migratory motor complex (MMC) MMC made of three sequences

Phase 1 – quiescence phase Phase 2 – random and irregular contraction phase Phase 3 – burst of uninterrupted phasic contractions

that last 5 – 10 minutes (activity front) Individual cycles last 1-2 hours Activity front can migrate from the antrum to ileum Stimulated by vagus nerve and motilin

Motor Response to a Meal On initiation of swallowing, the gastric

fundus relaxes to accommodate incoming food – mediated by the vagus nerve

Tone and phasic contractions are inhibited as meal enters the proximal stomach

Abolishes the cyclical MMC Accommodation results in 2-3 fold increase

in gastric volume Leads to retention of food in stomach until

it is distributed to the antrum

Liquid Meal Trituration of the meal is accomplished with

the propulsive force generated by the tonic contractions of the proximal stomach and the resistance of the antrum, pylorus and the duodenum

Liquids rapidly disperse through the stomach without a lag phase

Rate depends on volume, nutrient content and osmolarity Empty nutrient liquids empty quickly Rich nutrient liquids empty slower

Liquid Meal

Total stomach emptying time

Proximal stomach emptying time

Distal stomach emptying time

Solid Meals Solid meal emptying occurs in two phases

Initial lag phase Linear emptying phase

Solid component initially held in proximal stomach

As liquid empties, the solid components move to antrum for trituration

Lag phase causes redistribution of solids Restrict emptying of solid particles > 1mm

Solid Meals The antrum and pylorus grinds down

larger particles into smaller particles Then empties in linear fashion with

liquids The lag phase depends on size and

consistency of meal For typical western diet, the lag phase

is 60 minutes

Solid Meals

Total stomach emptying time

Proximal stomach emptying time

Distal stomach emptying time

Antropyloric motility Trituration is the function of coordinated

contractions High amplitude waves originate in proximal

antrum Propagate to pylorus At the midantrum point, the pylorus is open

permitting flow of liquids and liquefied solid particles

At the distal antrum, the terminal antral contraction closes the pylorus, promoting retropulsion of particles too large to exit the pylorus

Solid particles continue to move in and out of the antrum until it is broken down

Grinding and Emptying

Regulation of Gastric Emptying

Controlled by central and local neurohormonal control

Neuronal control includes: Intrinsic myenteric plexus Extrinsic postganglionic sympathetic fibers of the celiac plexus Preganglionic parasympathetic fibers of the vagus nerve

Vagus afferents can be relaxatory and excitatory

Hormonal control via CCK Relaxes fundic tone, decreases antral contraction and increase pyloric tone Also other hormones (glucagon like polypeptide, peptide YY) can control gastric emptying

Enterogastric Reflexes

Distension

Distension

RELAXATION

Gastric SecretionCell populations

Gastric epithelial cells Mucus and HCO3

Cells of the gastric glands Cells of the lamina propria

Mast cells: histamine Plasma cells: immunoglobulins

Neurocrine secretion E.g. ACh, VIP, somatostatin

Functional Gastric Anatomy

Cells of the Gastric GlandsGland type Cell type Secretory products

Cardiac Mucous Mucus, pepsinogen II

Endocrine e.g. D cells: somatostatin

Oxyntic Mucous Mucus, pepsinogens I and II

Parietal HCl, intrinsic factor

Chief Pepsinogen and Leptin

Enterochromaffin-like cells Histamine

D cells Somatostatin

Enterochromaffin ANP, serotonin, adrenomedullin

Pyloric Mucous Mucus, pepsinogens II

G cells Gastrin

enterochromaffin ANP, Serotonin

D cells Somatostatin

The Oxyntic and Pyloric Gland

HCl SecretionFunctions of gastric acid

1. Facilitate peptic hydrolysis of dietary proteins

2. Inactivate ingested microorganisms3. Facilitate intestinal absorption of

calcium, Vitamin B12 and iron

The Parietal Cell

Activation of the Parietal Cell

3 pathways:1. Neurocrine: Acetylcholine, released

from vagal efferences2. Endocrine: Gastrin, released from

antral G cells3. Paracrine: histamine, released from

mast cells and ECL cells

The Parietal Cell

Pathways of Activation of H+ Secretion

Mucosal nerves Mediate cephalic phase and response

to gastric distension ACh:

Stimulates parietal cell Stimulates gastrin release inhibits somatostatin release

Pathways of Activation of H+ Secretion

Gastrin Stimulated by:

Raised gastric pH Amino acids Gastric distension ACh

Stimulates histamine release via ECL cells and mast cells

Stimulates parietal cell directly

Pathways of Inactivation of H+ Secretion

Luminal H+ Gastrin release is inhibited once

gastric pH < 2.5 - 3 Somatostatin

Secretion is stimulated by gastric acid, gastrin and VIP

Inhibits histamine and gastrin release Inhibits histamine-mediated

activation of parietal cell

Pathways of Inactivation of H+ Secretion

Prostaglandins Autocrine secretion from macrophages

and endothelial cells of lamina propria Inhibit histamine-related parietal cell

activation Inhibit gastrin-related histamine release

TGF-alpha Vasoactive Intestinal Peptide (VIP)

Phases of Gastric Secretion

3 phases:1. Cephalic2. Gastric3. Intestinal

Cephalic Phase Vagally mediated stimulation of

the parietal cell Triggers:

Thought of food Sight Smell Taste and mastication

Gastric Phase

Distension Vaso-vagal and local reflexes

Parietal cell activation

High pH

Peptides

Caffeine

Gastrin

Mast cells

ECL cells

Histamine

Intestinal Phase

Distension

Hypertonicity

Carbohydrates

Fat

Low pH

Vago-vagal and local reflexes

Somatostatin

CCK

(-)

Pancreas

HCO3- SECRETIN

Patterns of Acid Secretion

Gastric Mucosa

Gastric Mucosal Barrier Mucous layer* HCO3*t

Epithelial tight junctions Mucosal blood flow*

* Modulated by prostaglandinst Stimulated by ACh

Mucoprotective Mechanisms

Esophageal Protective Mechanisms

Why is esophagus not damaged by reflux of fluid from the acid environment of the stomach?

Esophageal Peristalsis Contraction wave propagated down to the esophagus in

response to swallowing and distention clear acid bolus Saliva

pH of saliva is 6.4-7.8 which neutralizes acid Esophageal submucosal glands

In response to acid reflux from the stomach submucosal glands secrete bicarbonate rich fluid that neutralizes acid

Tissue Factors Esophageal epithelium with relatively “tight” limiting ionic

movement Esophageal stratified squamous epithelium is 25-30 cell layers

thick Na2+/H+ as well as Cl-/HCO3- transmembrane ion exchangers

remove hydrogen from the cell allow bicarbonate to enter cell In response to acid, blood flow increased to esophagus to clear

H+ and deliver HCO3-

Pepsinogens

Pepsinogen Pepsin

Proteins Peptides

Amino acids

H+

Stimulate acid secretion

Gastrin

Ach

Histamine

Secretin

Pepsin

Inactivated at pH>4

Somatostatin

Prostaglandins

CCK

_

+

Intrinsic FactorB12 – dietary protein

B12Dietary proteinR-binder

B12 - R

RB12 IF

B12 - IF

H+, pepsin

Pancreatic enzymes

Intrinsic Factor

Drugs Used in Acid-peptic Disorders

Acid-suppressive therapy Proton pump inhibitors (PPI’s) H2 receptor antagonists (H2RA’s) Antacids

Prostaglandin analogs Misoprostol

Prokinetics Domperidone Metoclopramide

Sucralfate and bismuth compounds

Acid-suppressive Therapy

H2 RA’s

4 types Cimetidine, ranitidine, nizatidine, famotidine Achieve ~70% acid suppression, especially

nocturnal Exceptional safety record Side effects

Antiandrogenic effect, hematopoietic, CNS, hepatic, prolonged QT if rapid infusion, ?immunomodulator

PPI’s 6 types

Omeprazole, esomeprazole, lanzoprazole, dexlanzoprazole, pantoprazole, rabeprazole

Mechanism of action1. Accumulation in the parietal cell2. Activation of the PPI by protonation3. Irreversible binding and inactivation of the H+/K+

ATPase

Side-effects: diarrhea, headaches Drug interactions

Secondary to P450 metabolism Secondary to achlorhydria

PPI’s – Practical Aspects PPI’s cannot be activated outside the

parietal cell Importance of parietal cell activation

Timing of PPI intake Timing of onset of action Impact of concomitant inhibitors of parietal cell

activity Bond to H+/K+ ATPase is irreversible Effects of chronic achlorhydria

Hypergastrinemia Bacterial overgrowth

Parietal Cell and PPI Interaction

H2RAPPI

Placebo

Objectives Describe the mucosal protective mechanisms of the

esophagus and stomach.

Illustrate the role of the stomach in the digestion of food.

Explain the processes making up normal gastric secretion.

Summarize the regulatory mechanisms controlling gastric digestion, secretion and emptying.

Summarize the process of normal gastric contractility and emptying.