Week 7 Gastrointestinal Physiology P1 PDF

Gastrointestinal Physiology_P1 May-17-2021 Copyright Notice • All materials found on Geisinger Commonwealth School of Medicine’s course and project sites may be subjecttocopyright protection,and mayberestricted from further dissemination, retention orcopying. • Disclosure • I have no financial re...

Gastrointestinal Physiology_P1 May-17-2021 Copyright Notice • All materials found on Geisinger Commonwealth School of Medicine’s course and project sites may be subjecttocopyright protection,and mayberestricted from further dissemination, retention orcopying. • Disclosure • I have no financial relationship with a commercial entity producing health-care related products and/orservices. • Class material and recording will be posted every Monday by 9.00 AM. House Keeping • Office hours are Tuesdays 8-9 PM. I will be meeting you individually by appointment to answer any questions you may have • I will be holding live case study sessions on Tuesdays and Thursdays 78 PM. Attendance is not mandatory, but highly recommended. These sessions will be recorded. Learning Objectives 1. Describe the structure of the GI wall; relate each layer to GI functions 2. Contrast the functional roles of sympathetic, parasympathetic, and the enteric nervous systems in regulating gut motility and peristalsis 3. Describe the storage, digestion, and motility roles of the stomach. 4. Distinguish proteins secreted into the gastric lumen by chief cells, parietal cells, and mucous cells. Contrast the functions and regulation of these secretions. 5. Explain factors that stimulate/inhibit hydrochloric acid secretion; relate to the causes of peptic ulcer including Helicobacter pylori and aspirin 6. Identify the major components secreted by the exocrine pancreas and the principal cell types involved in this secretion. Readings for this session: 1. Text Book; Chapter 8 (Pages; 339 - 366) 2. Class notes Gastrointestinal System • Integrated function of GI system: ▪ Coordinated movement of the food through the GI tract; mastication, swallowing, peristalsis, segmentation, contraction, and relaxation of sphincters. ▪ Secretion of enzymes, mucus, electrolytes and acid to aid digestion ▪ Absorption of water, ions, vitamins and nutrients ▪ Elimination of waste products • Integrated regulation by local, nervous, and hormonal systems. • GI system starts at the mouth → esophagus → stomach → small intestine (duodenum, jejunum, and ilium) → large intestine → anus. It also includes salivary glands, pancreas, liver and gall bladder that serve excretory functions. Cross-Section of Gastrointestinal Tract The “functional” cross‐section of the wall – ideal structure for: 1. Absorption of nutrients from lumen to blood supply 2. Secretion of gut hormones, HCL and enzymes for digestion 3. Conduit (ducts) for enzymes from the exocrine salivary glands, pancreas and liver 4. Movement of ingested food through the GI system; • Circular smooth muscle contraction decreases the diameter of the GI segment • Longitudinal muscle contraction decreases the length of the GI segment • Together they are responsible for the characteristic motility; peristalsis and segmentation 5. Master integrator - the enteric nervous system‐ receives sensory inputs from the gut & effector inputs from the SNS and PNS Longitudinal Section of Gastrointestinal Tract • Serosa is continuous with the mesenteries and consists of an enveloping layer of connective tissue that is covered with squamous epithelial cells. • Muscularis includes two layers of smooth muscles; • The inner layer is circular, • The outer layer is longitudinal, • Enteric neurons are present between these two muscle layers • Submucosa consists of loose connective tissue and larger blood vessels. Contains; • Submucosal Glands • Submucosal (Meissner’s) nerve plexus • Mucosa consists of the epithelial layer, as well as an underlying layer of loose connective tissue known as the lamina propria; contains capillaries, enteric neurons, and immune cells (e.g., mast cells), as well as a thin layer of smooth muscle known as the lamina muscularis mucosae (the muscle layer of the mucosa). Gastrointestinal Tract Mucosa • The surface area of the epithelial layer is amplified by several mechanisms; ▪ ▪ ▪ Most cells have microvilli on their apical surfaces, The layer of epithelial cells is evaginated to form villi and crypts (or glands), The mucosa is organized into large folds. • The epithelial cells serve absorptive and excretory functions, the shape and type of secretions differ according to the site of cells in the GI tract. Gastrointestinal Muscles • All of GI tract has smooth muscles, except; ▪ Pharynx ▪ Upper 1/3 of esophagus ▪ External anal sphincter • GI smooth muscles are of the visceral “unitary” type; where gap junctions ensure smooth and coordinated contraction • In comparison with skeletal muscle: Energy Low (up to 300x less) Force High Shortening High Time Long (tonic) Speed Slow • Many ways of stimulation; self excitatory, activated by stretch, hormones, local tissue factors • Nicotine, alcohol and caffeine can affect GI smooth muscle Membrane Potential in Intestinal Smooth Muscle Slow Waves: • Rhythmic changes in membrane potential initiated by interstitial cells of Cajal (pacemaker cells). • Specific frequency in each segment; 3/ min in stomach, 12/ min in small intestine, 8/ min in ilium, 11/ min in colon, 17/ min in rectum • → this determines the maximal possible frequency of contraction Spike Potentials: • Develop on top of slow waves when they reach threshold potential (~ -40 mV). • The higher the amplitude → the more spike potentials → the stronger the gut motility. At rest, sphincters maintain a positive pressure that is higher than the pressures in the adjacent organs; preventing both anterograde (forward) and retrograde (backward) flow. Enteric Nervous System (intrinsic): Think locally, act locally • Sensory information from GI system is received, integrated and responded to by ENS independently • Short reflexes that regulates GI: ▪ Secretion ▪ Motility (peristalsis, mixing contractions) ▪ Local inhibitory effects ▪ Growth • Myenteric plexus and Submucosal plexus are located in the gut wall and receive sensory signals from the gut lumen or the CNS • Although the enteric nervous system can function independently of extrinsic nerves, stimulation by the parasympathetic (PNS) and sympathetic (SNS) systems can greatly enhance or inhibit gastrointestinal functions Black Fibers - myenteric and submucosal plexuses. Red Fibers - extrinsic Control – SNS and PNS Green Fibers - afferent sensory fibers pass from luminal epithelium to the enteric plexuses: • Irritation of gut mucosa • Excessive gut distension • Presence of peptides, H+ Extrinsic Nervous System: Parasympathetic, Sympathetic Parasympathetic: • Vagus N: upper GI through ascending colon (including striated muscle of esophagus) • Both afferent and efferent limbs are contained in the Vagus nerve, and are called vagovagal reflexes Sympathetic: • Preganglionic fibers synapse outside GI tract. • Four sympathetic ganglia ▪ Celiac ▪ Superior and inferior mesenteric ▪ hypogastric • Post-ganglionic neurons are adrenergic (NE) • Pelvic N: Lower GI (colon and anal striated ms) • Adrenergic fibers may synapse with enteric plexuses or directly with smooth muscles, • Preganglionic fibers synapse in the walls of GI within the myenteric and submucosal plexuses. and mucosa (secretory and endocrine cells) • Post-ganglionic neurons are either cholinergic • NE causes relaxation of smooth muscles, contraction of sphincters and ↑ salivary (Ach), or peptidergic (VIP) secretion. • Information from PNS are coordinated in the enteric plexuses and relayed to smooth ms, endocrine and secretory cells. Reflex Control of the GI Tract Gastrointestinal Regulatory Substances Endocrine (Hormones): • Cells of the GI mucosa that are not concentrated in glands but are single cells or groups of cells dispersed over large areas, they pass through the portal circulation to the systemic circulation • Travel long way to act locally; ▪ Gastrin – causes acid secretion ▪ Gastric Inhibitory Peptide (GIP) “aka glucose-dependent insulinotropic peptide” → release insulin from ß cells of the Pancreas ▪ Cholecystokinin (CCK) ▪ Secretin Paracrines: • Act locally within the same tissue; ▪ Somatostatin – secreted by D cells of GI mucosa (in response to low PH) → inhibits H+ secretion ▪ Histamine (not a peptide) → stimulates H+ secretion Neurocrines: • Synthesized in neurons of the GI tract and released following stimulation • Released by either PNS (Ach and GRP), SNS (NE) or enteric plexuses (VIP, NO, & Enkephalins “opiates”) Gastric Motility Gastric motility aims at mixing and fragmenting food and mixing it with digestive enzymes, to be digested and absorbed. Two types of movements: Peristalsis: • Food bolus distends the gut wall, triggering a reflex contraction proximal to the food, and relaxation distal to the food; moving the food in the caudal direction Mixing of food: • Circular and longitudinal muscles alternate contraction and relaxation causing segmentation and pendular movements. • Mixing of food ensures: ▪ Chyme and digestive enzymes maintain uniform composition and texture ▪ Nutrients are in contact with epithelial cells for proper absorption Food Journey • Digestive System has four processes: 1. Ingestion and Swallowing: 2. Digestion and Secretion: is the chemical and mechanical breakdown of foods into smaller units that can be taken across the intestinal epithelium into the body 3. Absorption: 4. Motility and Defecation: • To maintain homeostasis, the volume of fluid entering the GI tract by intake or secretion must equal the volume leaving the lumen by absorption or excretion Chewing and Swallowing • Mastication, or chewing, mixes food with salivary mucus to lubricate it and facilitate swallowing, reduces the size of food parts, and mixes carbohydrates with salivary amylase to begin their digestion. • Swallowing has three phases: A. Oral Phase (voluntary): tongue positions food against hard palate. Entrance of the food initiates a swallowing reflex. B. Pharyngeal Phase (involuntary): 1. 2. 3. 4. Soft palate retract to close the nasopharynx Vocal cords are pulled together and the larynx is moved forward and upward against the epiglottis Upper Esophageal Sphincter (UES) relaxes to receive food bolus Superior constrictor muscles of the pharynx contract to force the bolus into the pharynx and through UES C. Esophageal Phase: is partly controlled by the swallowing reflex and partly by the enteric nervous system. Once food bolus passes UES, the reflex closes the sphincter to prevent reflux, and a primary peristaltic wave begins. Saliva • Three main groups of salivary glands: ₋ Parotids: produce water or serous saliva rich in enzymes ₋ Submandibular: serous and mucus elements ₋ Sublingual: produce mucus saliva In addition to Small Buccal Glands: antibacterial function • Salivary glands have unique high blood flow, that further increases with salivary glands stimulation • Saliva is composed of: ₋ Mucin, and water; moisturizes and lubricates the mouth and food, and aids tasting function and swallowing and speaking functions. ₋ Electrolytes help maintain calcium phosphate matrix of teeth (critical pH that favors tooth destruction is 5.5 and below) ₋ Thiocyanates, lysozymes; wash away bacteria and enzymatic bacterial attacks ₋ IgA antibodies; destroys bacteria (defensive system) ₋ α-amylase; early digestion of carbohydrates ₋ Lingual lipase; early digestion of fat ₋ Kallikrein; an enzyme that produces bradykinin (vasodilator) → causes vasodilation with salivary gl stimulation Formation and Regulation of Saliva • Acinar cells produce isotonic “plasma-like” saliva • Ductal cells modulate the initial secretion through ₋ Absorption of Na+ and Cl₋ Secretion of K+ and HCO3₋ Ductal cells are impermeable to water The resulting fluid is hypotonic (net absorption of solute) • At highest flow rate (4 mL/ min), saliva composition most closely resembles plasma and the initial saliva produced by the acinar cells. Regulation: • Salivary secretion is exclusively under neural control by the autonomic nervous system. • Salivary acinar cells and ductal cells have both parasympathetic and sympathetic innervation, both stimulating saliva production (parasympathetic control is dominant). • Stimulation of salivary cells results in increased saliva production, increased HCO3-, increased enzyme secretions, and contraction of myoepithelial cells to release saliva. Esophageal Motility • Primary peristalsis mediated by the swallowing reflex • If primary peristalsis does not clear the esophagus of food, a secondary peristaltic contraction, mediated by the enteric nervous system, is initiated (activated by mechanoreceptors) • Relaxation of Lower Esophageal Sphincter is mediated by Vagus nerve (VIP) and enteric nervous system • Simultaneously, orad stomach relaxes to receive the food bolus (receptive relaxation) • As soon as the bolus enters the orad stomach, the lower esophageal sphincter contracts, returning to its high-resting tone (preventing food from returning to esophagus) Disorders of Esophagus Achalasia is a motility disorder which is caused by spasm or failure to relax the lower esophageal sphincter (LOS) . This results in impaired flow of ingested food into the stomach and subsequent stasis of food and secretions in the esophagus. Results from the degeneration of the myenteric neurons that coordinate esophageal peristalsis and LES relaxation. Causes: Idiopathic, infection, syndromic Symptoms: dysphagia, regurgitation of undigested food, respiratory symptoms (nocturnal cough, recurrent aspiration, and pneumonia), chest pain, and weight loss Treatment – Block smooth muscle activation (L‐type Ca2+ channel blockers), Botulinum toxin (blocks Ach release from nerve terminals) is directly injected into the LES through a sclerotherapy needle; endoscopic –dilatation with air‐filled balloons Disorders of Esophagus Chronic gastric reflux (GERD) is the recurrent acid reflux into the esophagus. Causes: obesity/ overweight, iatrogenic (asthma, Ca2+ channel blockers), pregnancy or Hiatal hernia Symptoms: the most significant and frequent symptom is heartburn. May also include nausea, bad breath, decay and difficulty swallowing. Complications: caused by the long-term inflammation of the esophagus; esophageal stricture, Barrett’s esophagus “cells lining the esophagus can change into cells similar to the lining of the intestine” which may develop into cancer. Treatment – Antacids, proton-pump inhibitors, surgical corrections, life-style modifications (smoking, healthy diet, weight loss). Gastric Motility 1. Fill: LES and orad stomach relax (receptive relaxation), a Vagovagal event; mechanoreceptors detect distention → Vagal sensory afferent to CNS → Vagal efferent → post-synaptic neurons release VIP → relaxation 2. Churn: Gastric slow waves (3-5 per min), starting in the middle of the body causing strong peristaltic contractions to mix food. Food is not propelled as pylorus is closed. • Ach, gastrin → ↑ AP frequency and force of contraction • NE, secretin, GIP → ↓ AP frequency and force of contraction 3. Gastric Emptying: (~ 3 hrs) closely regulated to allow time for neutralization of gastric H+ in duodenum, digestion and absorption of nutrients. • Liquids empty more rapidly than solids. Retropulsion in the stomach continues until solid food particles are reduced to 1 mm3 or less. • Two major factors slow gastric emptying (i.e., increase gastric emptying time): (1) the presence of fat and (2) the presence of H+ ions in the duodenum. Gastric Secretions • Mucous Cells: secrete mucin and HCO3- to protect gastric mucosal lining from acid or irritants • Parietal Cells: Secrete; • HCl (H+): denatures proteins and activates pepsinogen to pepsin • Intrinsic Factor (IF): binds vitamin B12 to be absorbed in the terminal ilium • Chief Cells: Secrete pepsinogen • H+ activates it to Pepsin → digests proteins → Peptide fragments (oligopeptides) & amino acids i.e. Protein digestion starts in stomach. Pepsin also destroys bacteria or viruses in the food. • G Cells (endocrine cells): secrete Gastrin; gastric mucosa stretch by food/ proteins → activates G cells → Gastrin secretion into the blood HCl Secretion Cellular Mechanism: 1. CO2 + H2O → H2CO3 (carbonic anhydrase) easily dissociates into H+ and HCO32. At apical membrane, H+ is secreted into the lumen of the stomach via H+ - K+ ATPase. Cl- diffuses through Cl- channels. 3. At Basolateral membrane, HCO3- is absorbed in blood by the Cl- - HCO3- exchanger (responsible for alkaline tide) Net secretion of HCl and net absorption of HCO3- Regulation of HCl Secretion Rate of H+ secretion is regulated by either action of a single agent, or through interaction of more than one agent (potentiation). This interaction could be in the form of: • Distinct receptors/ second messenger • One stimulus (e.g. Ach) stimulates the release of another (e.g. histamine) Regulation during a single meal: • Vagus nerve action is facilitated through both Ach and Gastrin Releasing Peptide (GRP) • Alcohol and Caffeine → ↑ HCl secretion • NSAIDs block prostaglandin synthesis; • ↑ HCl secretion • ↓ mucus Peptic Ulcer Gastric (peptic) ulcer is erosion of the mucosal barrier by H+ and pepsin; • Most common: H Pylori • Excess stress • NSAIDs • Rarely: Zollinger-Ellison Syndrome Zollinger-Ellison Syndrome • Gastrinoma (Gastrin-releasing tumor) • ↑↑ Gastrin → ↑↑ HCl production and increased parietal cell mass Normally, Gastrin secretion by G cells is inhibited by ↑ H+, but the tumor secretes Gastrin autonomously • Ulcer may also be found in the duodenum as the excess H+ production exceeds buffering capacity, inactivates pancreatic lipase and may result in steatorrhea • Treatment: • Cimetidine • Omeprazole • Surgical removal of the tumor Helicobacter Pylori • bacteria • • Gram negative H. Pylori colonize antrum. H. Pylori produce urease which converts urea to CO2 and NH3. Ammonia neutralizes gastric acid and generates favorable environment to grow. H. Pylori then binds to gastric epithelium and damage them. • Local immune system fights infection → leaving further damage → overtime, mucus secreting epithelia diminish • Diagnosis: through symptoms (sharp stomach pain, bloating, burping, not feeling hungry, nausea and vomiting, dark blood in stool) and: • • • • Blood Tests: detection of anti-H. Pylori antibodies Blood in stool test Breath Tests: detecting 13CO2 in breath using 13C-urea Treatment: • Symptomatic: reduce acid effect on damaged mucosa • Curative: antibiotic therapy specific to the organism Delayed Gastric Emptying • Causes: • Idiopathic • Surgical (iatrogenic) • Neuropathy: 20-30% of diabetic patients develop delayed gastric emptying, mainly due to autonomic neuropathy • Symptoms: • Pain • Belching • Vomiting • Bloating • Treatment: • Drugs; antiemetics, prokinetics • Pyloric injection of botulinum toxin • Pyloroplasty • Gastric electrical stimulation Increased Gastric Emptying (Dumping Syndrome) Fluid and gastric content shift fast to small intestine, especially when ingesting high osmolarity of simple carbs in the duodenum (after both table sugar or fruit sugar) • Causes: • Bariatric Surgery • Gastric Surgery for peptic ulcers • Symptoms: ~ 30 minutes after food intake; • Abdominal cramping • Diarrhea • Flushing and sweating • Dizziness and lightheadedness • Tachycardia • Nausea • Treatment: • Dietary changes after surgery (eating smaller meals and limiting high-sugar foods) • Drinking fluids only between meals • If these dietary modifications fail to solve the problem, medications may be needed Vomiting Reflex (1) Vomiting is the oral expulsion of gastric (and sometimes duodenal) contents. Vomiting is usually a serious of events; (1) Nausea is typically associated with decreased gastric motility and increased tone in the small intestine, with reverse peristalsis in the proximal small intestine. (2) Retching ("dry heaves") refers to spasmodic respiratory movements conducted with a closed glottis. Gastric contents are forced into the esophagus but not the pharynx (as UES is closed). When retch is over, gastric contents may return to the stomach because LES is open. (3) Emesis is when gastric and often small intestinal contents are propelled up to and out of the mouth. • Causes: Vomiting is sometimes a protective reflex, and in many cases is caused by diseases outside GI tract • Somatic • Psychogenic (odors, fear) • A Vomiting Center in the Medulla coordinates the Vomiting Reflex Vomiting Reflex (2) • Afferent: • The back of the throat • GI tract, through SNS and PNS; sending information about the GI tract status, e.g. GI distention (a strong stimulus) or mucosal irritation. It also includes information from the heart (ischemia) or bile duct (stone) • Chemoreceptor trigger zone lying under the floor of the fourth ventricle (in brainstem). chemical abnormalities in the body (e.g. emetic drugs, uremia, hypoxia and diabetic ketoacidosis) are sensed by these centers, which then send excitatory signs to the vomiting center. Many of the antiemetic drugs act at the level of the chemoreceptor trigger zone. • Extramedullary centers in the brain could also sense certain psychic stimuli (odors, fear), vestibular disturbances (motion sickness) and cerebral trauma and could result in vomiting. • Efferent: • Reverse peristalsis that begins in the small intestine • Relaxation of the stomach and pylorus • Forced inspiration and contractions of abdominal muscles to increase abdominal pressure • Movement of the larynx upward and forward and relaxation of LES • Closure of the glottis (to prevent chyme from entering airways) • Forceful expulsion of gastric contents • Simple vomiting is usually self-limited and causes no problems Vomiting Reflex (3) • Excessive vomiting: • Aspiration pneumonia • Dehydration • Hypovolemia • Electrolyte imbalance “Hypokalemia” • Disturbance of acid-bas balance’ Loss of H+ and Cl → hypochloremic metabolic alkalosis • Projectile vomiting: • More sever than usual vomiting • Not preceded by nausea • Forceful • Travels few feet away from the body • May lead to dehydration if not properly treated