MBBS Year 1 GI Lecture Notes - Prof GE Mann PDF

MBBS Year 1 Gastrointestinal Physiology Lectures Prof GE Mann Notes for Lectures 58, 60, 61, 62 and 68 (Email: [email protected]) Lecture notes for each of Prof GE Mann’s GI Lectures 1-5 aim to provide students with a summary of concepts/information delivered in each of the narrated powerpoin...

MBBS Year 1 Gastrointestinal Physiology Lectures Prof GE Mann Notes for Lectures 58, 60, 61, 62 and 68 (Email: [email protected]) Lecture notes for each of Prof GE Mann’s GI Lectures 1-5 aim to provide students with a summary of concepts/information delivered in each of the narrated powerpoint lectures. Please note that these lecture notes do not provide a running written commentary for each of the slides presented. These notes hopefully will facilitate your learning of this fascinating topic in medicine. L1: OVERVIEW OF THE DIGESTIVE SYSTEM Learning Objectives Describe functions of the layers of the gastrointestinal (GI) tract: serosa, muscularis externa, submucosa, and mucosa Explain the physiological functions of salivary, gastric and pancreatic secretions Describe the mechanisms regulating digestion and absorption of nutrients Describe the endocrine control of the gastrointestinal tract Describe the physiological mechanisms that regulate the secretion of bile and role of the enterohepatic circulation Note introductory lecture provides an overview for subsequent GI lectures Introduction Microscopically the structure of the GI tract reflects the sequential functional changes that occur to ingested food as it passes from the mouth to the anus. Involuntary muscular contraction (peristalsis) is the primary propulsion force. Food is digested en route by enzymes secreted by the mucosae in fluids of appropriate pH and ionic composition. Endocrine cells releasing hormones are diffusely distributed GI epithelium. Locally produced hormones, such as gastrin and cholecystokinin affect the physiological activity of the GI tract. Food is initially digested during passage through the mouth and stomach with primary absorption of nutrients (amino acids, peptides, sugars and fats) occurring in the intestine. Salivary and gastrointestinal fluid secretions are largely reabsorbed. Undigested material is eliminated by the combined activity of involuntary and voluntary muscles. Subdivision of GI tract and its common features After mouth, digestive tract differentiated into 4 major organs: esophagus, stomach, small intestine and large intestine. Organs separated by muscular valves or sphincters, with mucosal layer lining the inner surface of the digestive tract. Digestion of carbohydrates initiated in oral cavity through amylase, and majority of digestion and absorption of carbohydrates and amino acids occurs across the mucosae of the stomach and small intestine. Secretions from the exocrine pancreas (e.g. HCO3) and liver (bile salts) pass directly into the lumen of the small intestine. Lymphatic vessels are distributed throughout the tract and involved in intestinal absorption of dietary fat. Histological organisation of the digestive tract With exception of the oral cavity, 4 concentric layers of muscle make up the GI tract from the esophagus to the large intestine: from lumen outward, these are mucosa, submucosa, muscularis and adventitia of the serosa Mucosa comprised of superficial epithelium, underlying stroma with vascularised loose connective tissue rich in immunocompetent cells (lamina propria) and a relatively thin layer of smooth muscle (muscularis mucosae). Smooth muscles in the latter layer are subdivided into an inner circular and outer longitudinal layers. Contractions of the muscularis layer throws mucosa into folds and ridges. Submucosa: Large blood vessels, lymphatic vessels are present, nerves send fibres into the mucosa and muscularis layers. Referred to as MESSNER'S PLEXUS. 1  Muscularis externa: Two layers of muscle, smooth type except the upper esophagus and anal sphincter, where striated muscle fibres exist. Inner circular layers surrounded by outer longitudinal layer, circular layer constricts the lumen, and longitudinal contractions shortens digestive tube. At sphincter points the circular layer is thickened. Adventitia or serosa: Several layers of loose connective tissue, alternately collagenous and elastic, covered by a thin layer of mesothelial cells. Circulatory and lymphatic vessels for nutrient supply and removal Largest arteries run longitudinally in submucosal layer, smaller branches in serosal layer. In muscularis layer, capillaries run parallel to muscle fibres. In mucosa the arteries supply an irregular capillary plexus around glands, sending terminal branches to the mucosal villi (lumen of intestine). Generally capillaries are fenestrated in the intestinal and exocrine epithelium. Veins arising in the mucosa anastomose in the submucosa and pass out of the intestine alongside arteries. Lymphatic vessels arise as blind tubes in the mucosa, known also as a lacteal vessel. Similar to blood capillaries they contain pinocytotic vesicles that shuttle macromolecules and chyclomicrons from the interstitial space into the lymphatic circulation. In submucosa, larger lymphatics branch freely, cross muscle layers, spreading into intermuscular tissue and serosa. Vascular and lymphatic vessels aid nutrient absorption. Moreover, epithelial tissue requires a continual supply of nutrients for cell maintenance and repair. Innervation of the GI tract Both autonomic motor and sensory fibres are found in gastrointestinal tract (GI). Motor fibres are both parasympathetic & sympathetic, ramifying throughout GI tract forming a plexus in each layer. Intramural parasympathetic ganglia: submucosal plexus (MEISSNER) and between 2 layers of muscularis externa in myenteric plexus of AUERBACH. Irregular pattern, input stimulates motor & secretory activity of the gut. Sympathetic innervation: fibres terminate in the submucosal and myenteric plexus and cause constriction of blood vessels, inhibit contraction of muscularis externa but constriction of muscularis mucosae. Endocrine control of the GI tract Influence of gut hormones on the alimentary tract: neurocrine, paracrine and endocrine control. Endocrine cells are widely distributed in epithelia of stomach, small and large intestine, appendix, distal esophageal glands and even ducts of pancreas and liver. Reference Source (see also recent Editions): Physiology, 5th Edition, eds. RM Berne, MN Levy, BM Koeppen, BA Stanton (2004-) (see sections in Chapters 32-34). Note there are also more recent editions in the library L2: DIGESTION AND ABSORPTION OF NUTRIENTS Learning Objectives Describe the digestion of protein, carbohydrates and fat from mouth to colon Describe mechanisms involved in intestinal absorption of carbohydrates, proteins, fats: uptake sugars, amino acids, dipeptides and fats Describe the role of pancreas and liver in the digestion of fat Describe possible clinical consequences of malabsorption of nutrients Intestinal uptake of amino acids, sugars and peptides Macromolecular nutrients digested in lumen of small intestine largely by pancreatic enzymes. Terminal digestion of proteins and carbohydrates by intestinal enzymes in mucosal surface. Amino acids, di- & tri-peptides, monosaccharides, fatty acids, monoglycerides absorbed, exocrine electrolyte secretions from salivary gland, stomach, pancreas, liver also reabsorbed. Small intestine is comprised of duodenum, jejunum, ileum. Entire small intestinal lining thrown into folds, surface studded with villi, 2 providing an enormous exchange area. At the base of these folds are tubular invaginations extending to muscularis mucosae, and in the pits are crypts of Lieberkuhn, which have generative and secretory functions. Upper duodenum contains Brunner glands in submucosa, secreting neutral or alkaline mucous into crypts in response to parasympathetic stimulation and feeding. Mucosal villi: each contains an arteriole, capillary network, vein, central lymphatic or lacteal. Capillaries ramify through the lamina propria and are closely apposed to basement membrane of absorptive epithelium. Fenestrated mucosal capillaries (98-103 km/100g, surface area 1.9-2.4 m2/100g tissue). Monosaccharide transport: Na+-sugar coupled uptake mechanism at mucosal interface, energy provided by Na/K-ATPase pump located at basolateral membrane, with sugar exit across serosal membrane mediated by a facilitated carrier into the interstitium and circulation to the liver. Stereospecificity of mucosal and basolateral sugar carriers differs. Amino acid transport: specific mucosal and basolateral carriers for amino acids with mucosal uptake via co-transport usually dependent on Na+ gradient from lumen to cell, structural specificity of parallel carrier systems recognising neutral, acidic, basic amino acids. Basolateral entry mechanisms primarily Na+-independent facilitated transport proteins and provide nutrient supply for epithelial renewal (especially during prolonged starvation where muscle protein breaks down and supplies amino acids across the basolateral cell region of intestine). Di-, Tri- and Tetra-peptide transport: protein in the chyme from the stomach can also be absorbed from the intestinal lumen as di-, tri- or tetra-peptides and hydrolysed to single amino acids by intracellular peptidases in the enterocyte. Uptake across the intestinal mucosa is an active process driven not by the Na+ gradient, but by a H+ gradient. Thus, oligopeptide uptake occurs via a H+/oligopeptide cotransporters referred to as PepT1. Once the oligopeptides are hydrolysed into constituent amino acids, the latter are transported out of the enterocyte across the ‘basolateral’ membrane facing the capillaries. A Na+/H+ exchanger on the brush-border membrane maintains the H+ gradient for H+/oligopeptide cotransport. Note that update of for example glycylglycine is “faster” than uptake of the single amino acid glycine – referred to as ‘kinetic advantage’. Intestinal absorption of fat: Glycerol, short-chain and medium-chain fatty acids can pass through enterocyte and enter blood capillaries due to their small size (e.g. pass across fenestrated capillaries). Triglycerides are broken down in the GI tract to free fatty acids and monoglycerides, which are embedded in micelles, make contact with the brush-border membrane of the small intestine and are passively absorbed into the epithelial cells. Absorption of fat is completed by the time chyme reaches the end of jejunum and bile salts set free from micelles to be reabsorbed primarily in the ileum and returned to the liver. In the small intestinal epithelium, cholesterol, phospholipids and fat soluble vitamins are incorporated into the centre of chylomicrons (see further notes below on lipid digestion), which have a ‘hydrophilic shell’. Chylomicrons are transported via the intestinal lymph to reach the systemic circulation. Pancreatic lipases and biliary bile salts, lecithin and cholesterol adsorb to the surface of emulsion droplets arriving from stomach. These lipolytic products (monoglycerides, fatty acids - including long- chain from gastric lipolysis are now ionized at alkaline, duodenal pH, lysolecithin and cholesterol act as further emulsifiers). Mixed micelles are composed of bile salts and mixed lipids, i.e. fatty acids, monoglycerides, lysophospholipids and cholesterol. Intestinal absorption of fat and water soluble vitamins There are two different types of vitamins: fat-soluble and water-soluble vitamins. Fat-soluble vitamins include A, D, E and K. Water-soluble vitamins are known as the vitamin B-complex group: thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), vitamin B6 (pyridoxine), folate (folic acid), vitamin B12, biotin and pantothenic acid, and vitamin C. Each of the water-soluble vitamins appears to require its own membrane transport process for absorption across the enterocyte. All water-soluble vitamins are absorbed from the small 3  intestine (see example in lecture using the Na+ gradient BUT not key to know each mechanism for each vitamin), folate, biotin, and riboflavin can be transported across colonic epithelial cells, with uncertain clinical significance. Fat soluble vitamins are carried by micelles to the brush-border membrane of intestinal villi where they then leave the micelle and diffuse across the lipid bilayer into the enterocyte. Within the enterocyte, they become incorporated into chylomicrons and then via the lymphatics to the bloodstream and eventually the liver. Apart from micelle formation, another important intraluminal event is that hydrolysis of cholesterol and fat soluble vitamins must occur before absorption takes place. L3: SALIVARY, GASTRIC AND PANCREATIC SECRETIONS Learning Objectives Name the salivary glands and the major kinds of salivary secretions and their function Describe how salivary secretion is controlled Describe factors which influence gastric juice secretion and concentration of HCl in stomach Explain how mucus and bicarbonate secretion create a gastric mucosal barrier Describe basal, cephalic, gastric and intestinal phases of acid secretion Describe the constituents and physiological functions of pancreatic juice Describe the factors causing release of secretin and cholecystokinin and how these intestinal hormones modify the composition of pancreatic juice Salivary secretion: Salivary glands are compound organs that secrete electrolytes and proteins (e.g. amylase) as a fluid into the oral cavity. Saliva lubricates food for swallowing and glycoproteins secreted from submandibular, sublingual glands, buccal glands aid in starch digestion. Maximum rate of saliva flow in humans ~1 ml/min.g. Vasculature is highly fenestrated and a 5-10-fold increase in blood flow during neural activation of salivary secretion guarantees sufficient supply of water, electrolytes and nutrients to sustain epithelial cells and active salivary secretion. Note that salivary blood flow is ~10 times that of an equal mass of contracting skeletal muscle. Microvascular arrangement: parallel capillary networks supplying acinar and ductal epithelial cells. The salivary glandular epithelium is comprised of specialised groups of cells called acinar cells, arranged as endpieces surrounding small central lumen, opening into ductule-striated or intercalated duct, which in turn converge into large ducts and open into main excretory ducts draining into mouth (e.g. sublingual-cheek, submandibular-below tongue). Parasympathetic stimulation mediated via chorda lingual nerve, evoking a marked fluid secretion accompanied by increased blood flow and oxygen consumption. Secretion of saliva, but not blood flow, blocked by atropine (co-release of VIP or substance P from cholinergic fibres mediates atropine-resistant increase in blood flow). Although blood flow increases 5-10-fold, salivary secretion is not due to increased hydrostatic pressure gradient from blood to saliva. Sympathetic activation generally causes vasoconstriction and scanty viscous secretion rich in proteins. b-adrenergic stimulation leads to a secondary reactive hyperaemia. Salivary secretory mechanism: reflex response controlled by parasympathetic and sympathetic nerves. Stimuli for salivary secretion include taste, touch and smell of food. Saliva formed by 2 stage process in which isotonic primary fluid (plasma-like electrolyte composition) formed by acinar cells is modified in the striated duct system by reabsorption of Na+ & Cl- and secretion of K+ and HCO3-. Micropuncture techniques confirm isotonic primary fluid. Patch-clamp evidence confirms neurotransmitters and hormones act on basolateral membrane of acinar epithelial cells to elevate intracellular Ca2+, which leads to activation of K+ channels in basolateral membrane and possibly Cl- channels in luminal membrane. Stimulus evoked loss of KCl and reuptake via basolateral Na+-K+-2Cl- co-transporter dependent on Na+-K+ pump. Rate of Cl- uptake directly linked to cycle of K+ release and reuptake. In steady state, three basolateral transport proteins are operative: K+ channel, Na+-K+ pump and the Na+-K+-2Cl- co-transporter operating to transfer Cl- into cell, with Cl- exit into lumen 4 (negative charge) across apical membrane. Na+ follows through paracellular space drawing water through and between cells by osmotic force. Cl- & K+ conductance increases when stimulation stops and the Na+-K+ pump and co-transporter restore intracellular KCl concentrations. Swallowing reflex: Voluntary phase of swallowing is initiated following separation of bolus of food in mouth from the mass in the mouth with tip of tongue. Bolus is moved upwards and backward by pressure of tongue against hard palate, forcing bolus into esophagus, activating tactile receptors that initiate the swallowing reflex. Pharyngeal phase of swallowing involves pulling of soft palate upwards, inward movement of palatopharyngeal fold toward one another, preventing reflux into the nasopharynx. Vocal cords pulled together, epiglottis covers the opening to larynx – both prevent entry of food into trachea. Upper esophageal sphincter relaxes to receive food, pharynx contracts strongly to force bolus deep into pharynx. Persistaltic waves now force food bolus through relaxed esophageal sphincter. Gastric secretion: Stomach is an exocrine organ, secreting a large acid volume after meal. Secretion also contains pepsin which initiates protein digestion, a process continued in the intestine by pancreatic enzymes. Gastric surface is protected by thin film of mucous constantly produced by surface epithelial cells. Another exocrine product is intrinsic factor, a glycoprotein that combines with vitamin B12 aiding absorption in the ileum. Entire surface of glandular stomach is a simple columnar epithelium of surface mucous cells, which also line numerous tubular invaginations and gastric pits. Turnover rate of mucous cells is 2-6 days. Stomach layers: muscularis mucosa - thin layer smooth muscle arranged as 2 or 3 sublayers, separates mucosa from serosa. Submucosa - dense connective tissue, larger blood vessels, lymphatics, nerves. Secretion accompanied by increased mucosal blood flow. Muscularis - 3 primary layers: inner oblique, middle circular, outer longitudinal; myenteric nerve plexus of Auerbach occurs in thin connective tissue layer separating circular & longitudinal muscle, co- ordinates contractions for churning food. Serosa - outermost layer thin connective tissue plus mesothelium is continuous via the omenta with peritoneum. Divisions of gastric mucosa cardiac glands: mucous secretion, near esophageal end, tubular, highly-branched & coiled glands with few or no peptic or oxyntic cells. These glands secrete some electrolytes pyloric glands: constitute 15-20% of total gastric mucosal area. Resemble mucous cells in neck and base regions of oxyntic glands; secrete alkaline mucous juice and some electrolytes as Ca phosphate, bicarbonates, NaCl & KCl; characteristic deep gastric pits; at junction with duodenum a thickened circular muscle layer is found at the pyloric sphincter. 5 x 105 cells/sq. mm, predominant cell type in antrum of stomach; release by exocytosis into basal and lateral cell surfaces, involvement of contractile filaments and microtubules. oxyntic glands: occupy fundus and body of stomach, 75-80% of total gastric mucosa; numerous invaginations called gastric pits, 100 per sq.mm, 3-7 empty - into each pit, ca. 35 million in total. Oxyntic gland is the key site of gastric HCl secretion. 3 regions: isthmus - parietal & surface mucous cells, neck - parietal & mucous cells, base - chief cells (secrete pepsinogen), some endocrine cells. Gastrin producing cells (G-cells) have been localised by immunofluorescence in middle third of mucosa. In man parietal cells more abundant pylorus than cardiac region, chief cell distribution reverse. Surface mucous cells are made up of a simple columnar epithelium, secrete neutral carbohydrate- rich glycoproteins. The mechanism of granule release is poorly understood but aspirin, ethanol, stress & food are stimulants. Mucous neck cells mucous granules larger than surface granules, stem cells for epithelial replacement, usually 1 week renewal period, secrete acidic glycoproteins. Parietal or oxyntic cells secrete 0.1 N HCl, located predominantly in middle and upper part of gastric gland, 25 µM diameter with base bulging into lamina propria, numerous mitochondria, specialised intracellular canaliculi extending from lumen to basal cytoplasm, microvilli on lumen & canaliculi walls providing a greatly increased surface area. HCl secretion occurs along this internalised structure following 5 activation of basolateral membrane receptors by ACh, histamine and gastrin. Chief or peptic cells secrete protein in manner similar to salivary/pancreatic acinar cells. Chief cells synthesise & secrete pepsinogen, which is converted to pepsin in acid milieu. Parietal Cell Receptors and Regulation of Acid Secretion Gastrin released by G cells of antral mucosa and first part of duodenum into bloodstream which carries this hormone to the parietal cells (endocrine mechanism). Histamine released from enterochromaffin-like cells in lamina propria of oxyntic (acid secreting) mucosa in response to activation by gastrin acting on CCK2/gastrin receptors. Histamine released into extracellular fluid and subsequently diffuses to the parietal cells (paracrine mechanism). Original dogma was potentiation of acid secretion when 2 of these 3 agonists bind to their receptors on parietial simultaneously. Evidence from Prof Rod Dimaline (Univ. Liverpool) suggests that the key final mediator of acid secretion in man is histamine released from enterochromaffin-like cells. As discussed in Boron and Boulpaep (Edition 2003, pg 899 and Fig. 41-8), gastric acid secretion by parietal cells is inhibited by PGE2, probably by inhibiting histamine’s action at a site distal to the histamine receptor. PGE2 appears to bind to an EP3 receptor on the basolateral membrane of the parietal cell and stimulates G-alpha1, which in turn inhibits adenylyl cyclase. PGE2 may also act indirectly by reducing histamine release from ECL cells and gastrin from antral G cells. Gastric juice is a complex solution of acidic component (HCl) from parietal cells and alkaline component containing pepsinogen from peptic cells & electrolytes such as Cl, Na, K from several cell types. Parietal cells postulated to secrete hydrogen ions at constant concentration of ca. 150 mEq/L, variation of acid in juice depends on rate of non-parietal cell secretion of alkaline component. Mechanism of H+ secretion against enormous gradient (high in canaliculi) requires energy (luminal H+- K+-ATPase), generated in oxyntic glands by aerobic metabolism. ATPase theory suggests energy available from ATP hydrolysis transferred to protein carrier, moves proton against electrochemical gradient. Phases of Gastric Acid Secretion Acid secretion divided into basal (fasting) and stimulated (post-prandial) phases. 5 - 10% of maximal rate in man. Cephalic: activated by sight, smell, taste & chewing of food; mediated by efferent impulses through vagus fibres to stomach and abolished by vagotomy. Pavlov: "conditioned reflex can be established by appropriate pairing of an unconditioned stimulus, such as food, with a conditioned stimulus as a bell". Gastric: food enters stomach, distension and chemical composition of food factors evoking gastric phase of secretion. Distension of stomach stimulates reflex acid secretion without release gastrin: intramural and longer vago-vagal pathways. Intestinal: food entering intestine. Liver extract, peptone, amino acid mixtures effective stimulants of acid secretion. Acid secretion occurs after all extrinsic nerves between intestine and stomach severed but blood supply left intact. Intestinal acid, fat and hyperosmolar solutions inhibit acid secretion. Zollinger-Ellison Syndrome A rare condition in which one or more tumors form in your pancreas or the upper part of your small intestine (duodenum). These gastrinomas, secrete large amounts of the hormone gastrin, which in turn via the systemic circulation stimulates ECL cells to release histamine which then acts on H2 receptors on the basolateral surface of the parietal cells in the gastric epithelium causing increased HCl secretion. The excess acid then leads to peptic ulcers, as well as to diarrhea and other symptoms. Notably, acid peptic reflux disease is more common and may be more severe in patients with ZES. Gastric acid hypersecretion is associated with increased pepsinogen secretion, noting that in ZES patients pH values as low as 1 and 3.6 in the proximal and distal jejunum respectively, converting pepsinogens to proteolytically active pepsins, contributing to mucosal injury in the small intestine. 6 Regulation of pancreatic secretion Human pancreas 90-100 g: enclosed on its right by duodenal loop; overlies inferior vena cava & abdominal aorta & extends to hilus of kidney; anteriorly overlain by stomach. Head, body & tail of pancreas drained horizontally by main pancreatic duct which enters the duodenum through ampulla of Vater. Blood supply, lymphatics & nerves accompany duct system to finest termini in pancreatic acini (similar to salivary gland). Innervated by parasympathetic (vagus) & sympathetic. Mixed endocrine & exocrine gland with acinar cells forming 82% of volume; each acinus about 50 acinar cells which surround duct lumen-called centroacinar lumen. Pyramidal shaped cells whose apical cytoplasm packed with zymogen granules. Endocrine tissue accounts for approx. 2-4% of pancreatic mass, dispersed throughout exocrine tissue. Secretion of pancreatic juice: Highest rate of protein synthesis of any secretory tissue with exception of lactating mammary gland; aqueous component rich in HCO3 neutralises duodenal content & enzyme component; proteolytic enzymes - trypsinogen, chymotrypsinogen, procarboxy- polypeptidase, ribonuclease, deoxyribonuclease amylase - starch & glycogen; lipase - hydrolyses neutral fat into glycerol & fatty acids. Secretin elicits aqueous & cholecystokinin pancreatic enzymes & fluid secretion. Note that during digestive phases, secretion of pancreatic juice is approx.