MDS2031 Gastrointestinal System Notes PDF

MMSA SCOME Notes Database Elsa Cassar MDS2031- Gastrointestinal System Contents Overview of the...

MMSA SCOME Notes Database Elsa Cassar MDS2031- Gastrointestinal System Contents Overview of the function of the GIT................................................................................................................... 2 Chewing, Swallowing and Vomiting................................................................................................................... 5 Oesophagus Physiology......................................................................................................................................... 8 Gastric Secretion....................................................................................................................................................... 11 Pancreatic and Bile Secretion.............................................................................................................................. 14 Liver Function........................................................................................................................................................... 19 Digestion....................................................................................................................................................................22 Drug Metabolism....................................................................................................................................................26 Gastrointestinal Motility........................................................................................................................................29 Development of the Gastrointestinal Tract.....................................................................................................32 Embryology of the Liver and Pancreas............................................................................................................36 Oesophagus and Stomach.................................................................................................................................. 40 Duodenum and pancreas.................................................................................................................................... 44 Liver and Biliary System....................................................................................................................................... 46 Imaging..................................................................................................................................................................... 49 Small and Large Intestines...................................................................................................................................50 Peritoneum and Surface Anatomy................................................................................................................... 54 Patterns of Neurovascular and Lymphatic Supply.......................................................................................55 Rectum and the Anus............................................................................................................................................59 1 MMSA SCOME Notes Database Elsa Cassar Physiology Overview of the function of the GIT PowerPoint, Guyton pg. 797 to 806 → Main functions: Ingestion, mastication (chewing), propulsion, secretion of digestive juices and hormones, digestion, absorption, excretion and defence against pathogens → Sphincters: o Smooth muscle: Lower oesophageal sphincter, pyloric, ileocecal and internal anal sphincter o Striated muscle: External anal sphincter (voluntary) and upper oesophageal sphincter (involuntary) → Cross section of intestinal wall from outer surface inwards: Serosa, longitudinal smooth muscle, circular smooth muscle, submucosa and mucosa. In addition, sparse bundles of smooth muscle fibres, the mucosal muscle, lie in the deeper layers of the mucosa. → The gastrointestinal smooth muscle functions as a syncytium, with a large number of gap junctions that allow low-resistance movement of ions from one muscle cell to the next. Muscle bundles fuse with one another at many points, resulting in a branching latticework of smooth muscle bundles. → Contraction: o Sphincters: Are normally contracted, but occasionally experience complete relaxation o Blood vessels and airways: Are normally partially contracted and only experience slight changes in contraction. This is called tone (the normal level of firmness or slight contraction in a resting muscle) o Stomach and intestines: Phasically active. Experience fluctuations in level of relaxation. o Oesophagus and urinary bladder: Normally relaxed but occasionally experience complete contraction → Activity of muscle fibres is in two types: 1. Slow waves; 2. Spikes → Slow waves: Most gastrointestinal contractions occur rhythmically, which is determined mainly by the frequency of slow waves. They are not action potentials, but slow undulating changes in the resting membrane potential. Slow waves usually do not cause muscle contraction by themselves, except perhaps in the stomach. Instead, they mainly excite the appearance of intermittent spike potentials → Frequency of slow waves of potential varies along the GIT. In the stomach body, it is 3 waves/min, in the duodenum it is 12 waves/min and in the terminal ileum it is 9 waves/min. → Interstitial cells of Cajal: Pacemakers that create the bioelectrical slow wave potential that leads to the contraction of the smooth muscle. Enteric motor neurons release neurotransmitters that bind primarily to receptor expressed by these cells. 2 MMSA SCOME Notes Database Elsa Cassar → Spike potentials: True action potentials that occur automatically when the slow waves temporarily become more positive than -40mV. The higher the slow wave potential rises, the greater the frequency of the spike potentials. → Gastrointestinal smooth muscle fibres allow large numbers of calcium ions to enter along with smaller numbers of sodium ions, thus called calcium-sodium channels. Much slower to open and close, therefore action potentials have a long duration. → Electrical activity of smooth muscle in the GIT: o Resting: Slow waves (-50 to -40mV) o Contraction: Spikes and depolarisation that can go up to 0mV. Stimulated by stretch, acetylcholine, parasympathetics and hormones. This causes tonic contraction o Hyperpolarisation: Reaches below -60mV. Stimulated by norepinephrine, sympathetics and hormones. → Tonic contraction: Exhibited by some smooth muscle together with or instead of rhythmical contractions. It is continuous contraction that increases and decreases in intensity. It is caused by continuous repetitive spike potentials by hormones or other factors that bring about continuous partial depolarisation or by entry of calcium ions. → Stimuli evoke mechanical and chemical sensors that go to the enteric nervous system both directly, and also indirectly through the brain and spinal cord. The enteric nervous system then stimulates effectors that cause motility, secretion and blood flow. → Enteric nervous system: Nervous system of the GI tract, lying entirely in the wall of the gut, beginning in the oesophagus and extending all the way to the anus. It is divided into the myenteric/Auerbach’s plexus (outer, between circular and longitudinal layers) and the submucosal/Meissner’s plexus (in the submucosa) → The myenteric plexus controls the GIT contractions. Stimulation of this plexus causes an increase in tonic contraction, an increase in intensity and rate of rhythmical contractions and an increase in velocity of waves’ propagation. It also causes inhibition of the sphincter muscle. → The submucosal plexus (aka Meissner’s plexus) controls mainly gastrointestinal secretion and local blood flow. It causes local intestinal secretion, local absorption and local contraction of the submucosal muscle. → Sensory information from the GI tract sends afferent fibres to both plexus of the enteric system, as well as the prevertebral ganglia of the sympathetic nervous system, to the spinal cord and to the vagus nerves. → Neurotransmitters secreted by enteric neurons include Ach, norepinephrine, ATP, serotonin, dopamine, cholecystokinin, substance P, vasoactive intestinal polypeptide, somatostatin, leu-enkephalin, met-enkephalin and bombesin. → Acetylcholine excites gastrointestinal activity while norepinephrine and epinephrine (the latter is released by adrenal medullae into circulation) inhibit it. → Serotonin: Regulation of body temperature, sleep, mood, appetite, pain, sex, cognition, gastrointestinal and cardiovascular activities and peripheral secretions. 3 MMSA SCOME Notes Database Elsa Cassar → Disruption in serotonin (5-HT) balance leads to anxiety, depressive disorders, eating disorders, aggressive behaviour, addition and abuse disorders. → Beta-2 reception causes smooth muscle relaxation (e.g. in GI tract causing decreased motility, in the bronchi, and in the blood vessels, causing vasodilation, especially those to skeletal muscle) → Parasympathetic innervation: Divided into cranial and sacral divisions. Cranial parasympathetics are almost entirely in the vagus nerves. Sacral parasympathetics originate in S2-4, pass through the pelvic nerves to the distal half of the large intestine and all the way to the anus. Post-ganglionic neurons are located mainly in the myenteric and submucosal plexuses. More extensive near the oral cavity and anus. → Sympathetic activation usually inhibits smooth muscle function. The exception to this is the sympathetic innervation of GI sphincters, in which sympathetic activation tends to induce contraction of smooth muscle. They originate from T5-L2, enter the sympathetic chains and then pass to outlying ganglia (e.g. celiac and mesenteric ganglia). Mainly secrete NE. → Sensory innervation: Cell bodes in enteric nervous system or dorsal root ganglia. Stimulated by irritation, excessive distension or presence of specific chemical substances. Can cause both excitation and inhibition, depending on the conditions. → Hormones: Hormone Stimuli for Site of Action Secretion Secretion Gastrin Protein; G cells of the Stimulates gastric acid secretion Distention; GRP antrum, and mucosal growth (gastrin-releasing duodenum and peptide) jejunum Cholecystokinin Protein, fat and I cells of the Stimulates pancreatic enzyme acid duodenum, secretion, gallbladder contraction, jejunum and growth of exocrine pancreas. ileum Inhibits gastric emptying Secretin Acid and fat S cells of the Stimulates pepsin secretion, duodenum, pancreatic bicarbonate secretion, jejunum and biliary bicarbonate secretion and ileum growth of exocrine pancreas. Inhibits gastric acid secretion Gastric inhibitory Protein, fat and K cells of the Stimulates insulin release and peptide carbohydrate duodenum and inhibits gastric acid secretion jejunum Motilin Fasting M cells of the Stimulates gastric motility, duodenum and intestinal motility and inter- jejunum digestive myoelectric complexes → Incretins: Group of metabolic hormones that stimulate a decrease in blood glucose levels. Released after eating. Augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism. 4 MMSA SCOME Notes Database Elsa Cassar → The name incretin is derived from intestine, secretion and insulin → The two major incretins are GLP-1 and GIP → GLP-1: Produced by L cells mainly located in the distal gut (ileum and colon). Stimulates glucose-dependent insulin release. → Other effects of GLP-1 include suppression of hepatic glucose output by inhibiting glucagon secretion in a glucose-dependent manner; inhibition of gastric emptying; reduction of food intake and body weight and enhancement of beta-cell proliferation and survival in animal models and isolated human islets → GIP: Produced by K cells in the proximal gut (duodenum). Stimulates glucose-dependent insulin release as well. It has minimal effects on gastric emptying and no significant effects on satiety or body weight. Potentially enhances beta-cell proliferation and survival in islet cell lines. → Peristalsis: Stimulated by distension of the gut. Innervated by the myenteric plexus. → Splanchnic circulation: Blood vessels of the GI system. Also includes the spleen, pancreas and liver. All the blood from the gut, spleen and pancreases flow immediately into the liver by the portal vein. Fats from the gut enter the lymphatic system and are conducted to the blood by the thoracic duct, thus bypassing the liver. → Counter current blood flow in the villi allows blood oxygen to diffuse out of the arterioles directly into adjacent venules, thus making it unavailable for local metabolic functions → Circulatory shock causes ischaemic death of villi which greatly reduces absorptive capacity → Summary of main concepts: o Interstitial cells of Cajal play a central role in slow wave generation o Calcium influx through channels in smooth muscle membranes dictates action potential generation in the GIT o The intestine secretes GLP-1 (L cells: glucagon-like peptide-1) and GIP (K cells: glucose-dependent insulinotropic peptide) which potentiate insulin secretion from beta cells and their proliferation o A complex interplay between the autonomic nervous systems, myenteric and submucosal plexuses and a number of neurotransmitters and hormones controls GIT functions Chewing, Swallowing and Vomiting PowerPoint (MP) → Chewing reflex: Bolus of food in the mouth → Inhibition of the muscles of mastication → Lower jaw drops → Stretch reflex of jaw muscles → Rebound contraction of muscles → Jaw raises, causing closure of the teeth → Tongue: Used my mammals to position food for grinding. Made up mainly of skeletal muscle, consisting of the tip, blade, dorsum/back and root 5 MMSA SCOME Notes Database Elsa Cassar → Mastication role: Progression of food, excoriation of GIT, enzymatic action and rate of digestion → Chewing is a voluntary motor activity controlled by the motor cortical areas and in the brainstem reticular areas through the motor component of the trigeminal nerve. Stimulation of the hypothalamus, amygdala and cerebral cortex near the sensory areas for taste and smell can often cause chewing. → Xerostomia: Dry mouth, associated with a change in the composition of saliva or reduced salivary flow (hyposalivation). → Hyposalivation: Side effect of many medications, more common in older people (because they tend to take several medications) and in persons that breathe through their mouths, in dehydration and in radiotherapy involving the salivary glands. It can also be of psychogenic origin. → Saliva is secreted by 3 pairs of extrinsic salivary glands and small intrinsic buccal glands → Saliva functions in cleansing the mouth, lubricating and protecting the oral cavity, dissolving food chemicals and moistening and compacting food. → Saliva prevents the deterioration processes by: o Washing away pathogenic bacteria and food particles that provide their metabolic support o Contains several factors that destroy bacteria such as thiocyanate ions and proteolytic enzymes, including lysozyme o Contains protein antibodies that destroy oral bacteria → Other functions include haptocorrin (aka TC-1/cobalophilin/R-protein/R-factor) which protects acid-sensitive vitamin B12; early digestion; antimicrobial activity; taste, thirst perception and vocalisation; tissue healing (growth factors e.g. Epidermal Growth Factor); adjustment to chemical nature of bolus and lubrication → Saliva contains large quantities of K+ and HCO3- and low concentrations of Na+ and Cl- compared to plasma. The acini secrete a primary secretion containing ptyalin and mucin, which flows through the ducts, during which Na+ is actively reabsorbed and K+ is actively secreted. This causes electrical negativity of -70mV, causing Cl- to be reabsorbed passively. Bicarbonate ions are secreted by the ductal epithelium into the lumen of the duct due to passive exchange of bicarbonate for chloride. → During maximum salivation, the salivary ionic concentrations change considerably because the rate of formation of primary secretion by the acini increases, and thus ductal reconditioning of the secretion is reduced. → Stimulation of parasympathetic nerves to the alimentary tract almost invariably increases the rates of alimentary glandular secretion, especially those in the upper portion of the tract (innervated by glossopharyngeal and vagus) e.g. salivary and oesophageal glands → Salivary glands are controlled by parasympathetic nervous signals from the superior and inferior salivatory nuclei, which are located approximately at the juncture of the medulla and pons and are excited by both taste and tactile stimuli from the tongue and other areas of the mouth and pharynx. 6 MMSA SCOME Notes Database Elsa Cassar → Salivation can also be stimulated or inhibited by nervous signals arriving in the salivatory nuclei from higher centres of the CNS, including the appetite area, which is located in proximity to the parasympathetic centres of the anterior hypothalamus. It functions to a great extent in response to signals from the taste and smell areas of the cerebral cortex or amygdala. → Salivation also occurs in response to reflexes originating in the stomach and upper small intestines, particularly when irritating foods are swallowed or when a person is nauseated because of some gastrointestinal abnormality., so as to remove the irritating factor. → Sympathetic stimulation can also increase salivation a slight amount. They originate from the superior cervical ganglia and travel along the surfaces of the blood vessel walls to the salivary glands. → Blood supply to the glands affects salivary secretion since it requires adequate nutrients from the blood. Parasympathetic nerves moderately dilate the blood vessels. → Salivation itself directly dilates the blood vessels, thus providing increased salivatory gland nutrition as needed by the secreting cells. Part of this additional vasodilator effect is caused by kallikrein secreted by the activated salivary glands. → Kallikreins are a subgroup of serine proteases (enzymes that cleave peptide bonds). Plasma kallikrein (KLKB1) has no known paralogue. Tissue kallikrein-related peptidases (KLKs) encode a family of 15 closely related serine proteases. They cause kininogens to form bradykinin, which causes vasodilation and increased permeability for increased secretion of saliva. → Summary of control of salivation: Average output of 1000-1500ml/day. Stimulated primarily by the parasympathetic division (salivatory nuclei and VII, IX nerves). Also triggered by sight, smell, though of food and irritations in the lower GI tract. It is stimulated by the kallikrein-bradykinin factors and inhibited by sympathetic division and dehydration. → Mucus: Provided by billions of single-cell mucous glands (aka goblet cells) present along the entire GIT → Features of mucus: Composition, lubrication, protection, adherent, coating, slippage, resistant to digestion, amphoteric properties and trapping network → Thick secretion composed mainly of water, electrolytes and several glycoproteins (large polysaccharides bound with protein). → The oral cavity is well-vascularised, thus drugs that are absorbed through the oral mucosa enter directly into the systemic circulation, hence having a rapid onset of action. Several cardiovascular drugs are administered transmucosally (e.g. nitro-glycerine) → The palate is supplied by the maxillary, sphenopalatine and greater palatine arteries → The floor is supplied by several arteries, including the sublingual branch of the lingual artery. → Buccal administration involves placement of the drug between the gums and the cheek. → Damage to CN V, CN IX and CN X can cause paralysis of the swallowing mechanism 7 MMSA SCOME Notes Database Elsa Cassar → Poliomyelitis or encephalitis can prevent normal swallowing by damaging the swallowing centre of the brain stem → Paralysis of the swallowing muscles which occurs in muscle dystrophy, myasthenia gravis or botulism can also prevent normal swallowing. → This paralysis can cause abrogation of the swallowing act, failure of the glottis to close (food thus passes into the lungs) or failure of the soft palate and uvula to close the posterior nares (food refluxes into the nose during swallowing). → Under deep anaesthesia, a patient my vomit large quantities of materials into the pharynx, then suck them into the trachea since the anaesthetic blocks the reflex mechanism of swallowing. As a result, such patients occasionally chock to death. 40% of deaths due to stroke are attributable to defects in the swallowing mechanism. → Aspiration pneumonia: Bronchopneumonia that develops due to the entrance of foreign materials into the bronchial tree (usually oral or gastric contents). Chemical pneumonitis can develop, and bacterial pathogens may add to the inflammation. → Cause is usually incompetent swallowing mechanism, e.g. due to neurological disease/injury, including multiple sclerosis, Alzheimer’s disease or intoxication. → Iatrogenic cause is during general anaesthesia; thus, patients are instructed to be nil per os (abbreviated as NPO) i.e. nothing by mouth for at least 4 hours prior to surgery. → Nervous control: Food bolus stimulates receptors in the pharynx. Impulses travel along sensory fibres of trigeminal and glossopharyngeal nerves. The signals are integrated in the swallowing centre (nucleus of the solitary tract, reticular substance of the bulb), causing: o Inhibition of respiratory centre in the medulla oblongata and pons, thus interruption of breathing to allow swallowing o Activation of the swallowing reflex (V, IX, X, XII) → Swallowing: Tongue thrust up and back, nasopharynx closed, larynx elevated, airway closed, UES opened and pharynx contracted. The swallowing mechanism involves more than 20 muscles → Upper oesophageal sphincter is made up of striated muscle that is not under voluntary control. It is relaxed (opens) by swallowing. Oesophagus Physiology PowerPoint (MP) → Oesophagus: Muscular 25cm tube. Collapsed when not involved in food propulsion. → Secretions: Simple and compound mucous glands. Main body of oesophagus is lined with simple glands while the top and bottom also have compound glands. Secretions are entirely mucous in character and principally provide lubrication for swallowing. → Compound glands: In the upper oesophagus, they prevent mucosal excoriation by newly entering food. At the oesophago-gastric junction, they protect the oesophageal wall from 8 MMSA SCOME Notes Database Elsa Cassar digestion by acidic gastric juices that often reflux from the stomach back into the lower oesophagus. → Peptic ulcers can occur at the gastric end of the oesophagus → Food traverses the oropharynx and laryngopharynx to reach the oesophagus → Musculature of the pharyngeal wall and the upper third of the oesophagus is striated muscle. Thus, peristaltic waves in these regions are controlled by skeletal nerve impulses from the glossopharyngeal and vagus nerves. In the lower two thirds of the oesophagus, musculature is smooth muscle, but this portion is still strongly controlled by the vagus nerve acting through connections with the oesophageal myenteric nervous system. → The oesophageal myenteric nervous system would still be able to cause strong secondary peristaltic waves without support from the vagal reflexes. Hence, even after paralysis of the brain stem swallowing reflex, food fed by a tube or in some other way into the oesophagus still passes readily into the stomach → Primary peristalsis: Continuation of the peristaltic wave that begins in the pharynx and spreads into the oesophagus during the pharyngeal stage of swallowing. It lasts 8 to 10 seconds, and 5 to 8 seconds if the person is upright. → Secondary peristalsis: Caused by the distention of the oesophagus itself sensed by stretch receptors when the retained food if the primary peristaltic wave fails to move all the food. These waves are initiated partly by the myenteric plexus system and partly by reflexes that begin in the pharynx and are then transmitted to the medulla by the vagus and back again to the oesophagus through glossopharyngeal and vagus nerve. → Food can reach the stomach even if the person is upside down → Lower oesophageal tract: Smooth muscle controlled by the dorsal motor nucleus of the vagus nerve. It is a functional sphincter (not anatomical) with histology distinct from the stomach. Can become dysfunction in achalasia, GERD, Parkinson’s. → Fluoroscopy: Imaging technique using X-rays to obtain real-time moving images of the interior of an object. Contrast (usually barium sulfate with water) is swallowed, since it enhances the visibility of the relevant parts of the GI tract by coating the inside and appearing white on the film. → Manometry: Test to measure the function of the oesophagus. Thin, pressure-sensitive tube is passed through the down into the stomach. Numbing medicine inside the nose. After the tube is in the stomach, it is pulled slowly back into the oesophagus and the patient is asked to swallow. Pressure of muscle contractions is measured along several sections of the tube. → Other studies can be done while the tube is in place. It takes about an hour. → Gastroesophageal reflux disease: Digestive disorder that affects the LES. Causes heartburn, chest pain or acid indigestion. → Hiatal hernia: Stomach bulges up into the chest through the hiatus. Can be sliding or paraesophageal. → Swallow syncope: Temporary loss of consciousness caused by a fall in blood pressure when swallowing. 9 MMSA SCOME Notes Database Elsa Cassar → Achalasia: Failure of smooth muscle fibres to relax, which can cause the lower oesophageal sphincter to remain closed. Marked reduction of NO and VIP-containing neurons in the myenteric plexus of the lower oesophagus and LES cause them to remain contracted, resulting in stasis of food, putrid infection, mucosal ulcerations and substernal pain. This might result in megaoesophagus (dilation of oesophagus) with possible rupture and death → Heartburn: Aka pyrosis, cardialgia or acid indigestion. Burning sensation in the chest which may radiate to the neck, throat or angle of the jaw. In pregnancy, the placenta secretes progesterone that inhibits gastric motility and causes smooth muscles relation in the uterus and LES, causing gastroesophageal reflux that results in heartburn. → Stomach functions: Storage, chyme formation, gastric juice secretion, digestion and absorption of alcohol/caffeine/aspirin/etc. → Vagovagal reflex: When the stomach is distended, the stomach stretch-receptors send impulses via vagal afferent nerves to the CNS, which sends back vagal efferent impulses to the enteric nervous system, activating inhibitory motor neurons and causing stomach muscle relaxation. → Stomach relaxation: A bolus in the pharynx and oesophagus causes the vagovagal reflex in the oesophagus which results in activation of inhibitory motor neurons releasing VIP which causes receptive relaxation of the stomach. This decreases gastric pressure to allow the bolus to enter the stomach where it activates the vagovagal reflex, causing adaptive relaxation of the stomach. → Malfunction of gastric relaxation reflexes result in reflux, weight loss and early satiety → Aspiration pneumonia: Bronchopneumonia that develops due to the entrance of foreign materials into the bronchial tree. Depending on acidity, chemical pneumonitis can develop → Slow waves propagate as a band toward the pylorus, activating contractions as smooth muscle cells depolarise, from the fundus to the corpus to the antrum and finally the terminal antrum. → Dominant pacemaker produces 3 cycles per minute while the antral pacemaker produces 1 cycle per minute. The frequency of the entire stomach runs at the frequency of the dominant (corpus) pacemaker → Stomach emptying: Intense contractions, beginning in mid-stomach and spreading through the caudad stomach. Strong peristaltic, very tight ring-like constrictions. At the stomach becomes progressively more and more empty, the constrictions begin farther and farther up the body of the stomach. → Emptying does not occur because of increased pressure since the increase in volume does not increase pressure much. It is because of the stretching of the wall and subsequent local myenteric refluxes that pyloric pump is accentuated → Chyme emerging from the stomach has a pH of approximately 2 → Gut-associated lymphoid tissue: GI tract’s immune system. Largest mass of lymphoid tissue in the human body. 10 MMSA SCOME Notes Database Elsa Cassar → Factors that activate the enterogastric reflex: Stretching of duodenal wall, irritation of duodenal mucosa, acidic chyme/protein/fat in the duodenum and hypertonic/hypotonic chyme in the duodenum. These factors inhibit the stomach’s contents from emptying into the small intestine. → Reflexes are sent from the duodenum to the stomach to slow/stop stomach emptying if the volume of the chyme is too much. These are mediated by three routs (1) enteric nervous system in gut wall; (2) prevertebral sympathetic ganglia; (3) vagus nerve. All three routes strongly inhibit the pyloric pump propulsive contractions and increase the tone of the pyloric sphincter, resulting in a decrease in stomach emptying. → Enterogastric inhibitory reflexes are especially sensitive to presence of irritants and acids in the duodenum. → Hormones released from the upper intestine also inhibit stomach emptying, mainly stimulated by fats. Fat chyme releases CCK while acidic chyme releases secretin. GIP is also released in response to fat and carbohydrates. All three hormones decrease stomach emptying. → Gastroparesis: Aka delayed gastric emptying. Partial paralysis of stomach, resulting in food remaining in the stomach for an abnormally long time. Can be caused by vagus nerve damage → Transient gastroparesis may arise as a consequence of type 1 or type 2 diabetes, anorexia nervosa, bulimia nervosa, Parkinson’s disease, mitochondrial disease, abnormal surgery and heavy cigarette smoking. → Nasogastric tube placement: For enteral feeling, medication administration, gastric decompression or to allow continuous aspiration of retained gastric contents. Gastric Secretion PowerPoint (MP), → Oxyntic glands: Also known as gastric glands. Secrete HCl, pepsinogen, intrinsic factor and mucus. Found in the body and fundus of the stomach (80%). Contains three main types of cells: 1. Mucous neck cells: Mucus 2. Peptic/chief cells: Pepsinogen 3. Parietal/oxyntic cells: HCl and intrinsic factor → Pyloric glands: Mainly secrete mucus, but also secrete gastrin. Located in the antrum of the pylorus (the distal 20% of the stomach). They are branched, coiled, tubular glands that open into the deep gastric pits. They lack chief and parietal cells. → Surface mucous cells: Secrete large quantities of viscid mucus. Cover the entire surface of the stomach mucosa. Mucus secretion is affected by aspirin, NSAIDs, PGE 2, adrenalin and stress. The mucus is alkaline. 11 MMSA SCOME Notes Database Elsa Cassar → Parietal cells of the oxyntic glands are the only cells that secrete HCl, with a pH as low as 0.8. Secretion is under continuous control by endocrine and nervous signals and by enterochromaffin-like cells (ECL cells) → Enterochromaffin-like cells: Primary function is to secrete histamine. Lie in the deep recesses of the oxyntic glands. Release histamine in direct contact with parietal cells. Rate of HCl production is directly related to histamine secretion. ECL cells are stimulated to secrete histamine by gastrin, which is formed in the antrum. Also stimulated by hormones. → Gastrin: Hormone secreted by gastrin cells (G cells) in the pyloric glands in the antrum. Large polypeptide secreted in two forms- G34 and G17 (numbers indicate the number of amino acids). Smaller form is more abundant. Some proteins stimulate G cells to secrete gastrin into the blood, to be transported to ECL cells, causing histamine release which stimulates HCl secretion. → High acidity in the antrum stimulates somatostatin release by D cells to inhibit meal- stimulated gastrin secretion. → Vagus nerve can stimulate Ach release to act directly and indirectly (by stimulating ECL cells) on parietal cells to release HCl. The vagus also acts on G cells via gastrin-releasing peptide) to stimulate gastrin release to stimulate further HCl release. → Parietal cells contain large branching intracellular canaliculi. HCl is formed at the villus- like projections inside these canaliculi and is then conducted through the canaliculi to the secretory end of the cell. → The main driving force for HCl secretion by the parietal cells is the H+-K+ ATPase. → HCl formation: 1. H+ enters from the parietal cell into the canaliculus lumen in exchange for K +, using ATP. K+ tends to leak back into the lumen. 2. At the basolateral end, Na+ is taken out from the parietal cell into the interstitial fluid in exchange for K+, resulting in low intracellular Na+. Therefore Na+ enters the parietal cell from the canaliculus lumen. Hence, most of the K + and Na+ is reabsorbed into the cell cytoplasm and H+ take their place in the canaliculus. 3. Pumping of H+ out of the cell allows OH- to accumulate within the parietal cell and bind with CO2 to form HCO3- by carbonic anhydrase. This is then transported into the extracellular fluid in exchange for Cl-, which enter the cell. 4. These Cl- are secreted through chloride channels into the canaliculus, binding with H+ to form HCl. This is then secreted outward through the open end of the canaliculus into the lumen of the gland 5. Water passes into the canaliculus by osmosis due to the extra ions being secreted into the canaliculus. Hence, the final secretion contains water, HCl (150- 160mEq/L), KCl (15mEq/L) and a small amount of NaCl. → Hydrochloric acid: Released at 150mM/L, pH of 0.8, isotonic and 1500cal/L. It functions in (1) conversion of pepsinogen to pepsin; (2) bactericidal; (3) Fe3+ reduction to Fe2+; (4) secretion and somatostatin release stimulation and (5) chyme formation and protein denaturation 12 MMSA SCOME Notes Database Elsa Cassar → Inter-digestive period: Stomach secretes a few millilitres of gastric juice each hour. Almost entirely of the non-oxyntic type, mainly mucus with little pepsin and no acid. → Emotional stimuli may increase inter-digestive gastric secretion, contributing to stress ulcers → Gastrin, CCK and secretin are all large polypeptides. Terminal 5 amino acids in gastrin and CCK are the same. → Pentagastrin: Synthesis gastrin composed of the terminal four amino acids to natural gastric plus the amino acid alanine. Has all the same properties as the natural gastrin. → Chronic gastritis: Stomach lining becomes inflamed. Can cause destruction of parietal cells, which results in achlorhydria (lack of stomach acid secretion) and pernicious anaemia (anaemia from lack of intrinsic factor) due to failure of maturation of RBCs in the absence of vitamin B12 stimulation of the bone marrow → Pernicious anaemia: Bacterial overgrowth and B12 deficiency. Can cause micronutrient deficiencies, resulting in visual changes, paraesthesia’s ataxia, memory defects, hallucinations, limb weakness, gait disturbance and personality/mood changes → Vitamin B12 sources: Eggs, milk, cheese, milk products, meat, fish, shellfish and poultry. Some soy products are fortified with vitamin B12. → Vitamin B12: Aka Cobalamin. Slight deficiency can lead to anaemia, fatigue, mania and depression. Long-term deficiency can cause permanent damage to the brain and CNS. Only manufactured by bacteria and only found naturally in animal products. Can be consumed in large doses because excess is excreted or stored (stores last for up to a year) → Role of the intrinsic factor: VitaminB12 finds to haptocorrin in the saliva, forming a complex that is resistant to gastric juice. In the proximal small intestine, the complex is cleaved by pancreatic enzymes. Vitamin B12 binds to intrinsic factor to form a complex that is resistant to proteolysis and absorption in the proximal small intestine. It is then absorbed in the ileum by receptor-mediated endocytosis, using cubilin. It is taken by portal blood to the liver where it is stored, or else it travels in the blood bound to transcobalamin II. → Helicobacter pylori: Causes peptic ulcer. Infects the antrum, causing inflammation (gastritis) which is often asymptomatic. This leads to a duodenal or gastric ulcer that can result in bleeding or perforation. → Pepsinogen: No digestive activity when secreted. Activated to pepsin by HCl (from 42,500 MW to 35,000). It has no proteolytic activity above pH of 5. → Three phases of gastric secretion: 1. Cephalic: Before food enters the stomach. Sight, smell, thought or taste. Signals originate in the cerebral cortex and appetite centres of amygdala and hypothalamus. Transmitted through dorsal motor nuclei of vagi and then through vagus nerves to the stomach. Accounts for around 30% of gastric secretion 2. Gastric: Food excites the long vagovagal reflexes, the local enteric reflexes and the gastrin mechanism. Around 60% of secretion. 3. Intestinal phase: Presence of food in the duodenum, accounting for 10%. 13 MMSA SCOME Notes Database Elsa Cassar → Inhibition of gastric secretion: Intestinal chyme slightly stimulates gastric secretion during early intestinal phase, but inhibits it at other times: 1. Presence of food in small intestines initiates reverse enterogastric reflex, transmitted through myenteric nervous system and extrinsic sympathetic and vagus nerves, which inhibit stomach secretion. This reflex can be initiated by distension of small bowl, presence of acid or protein breakdown product or irritation of the mucosa. 2. Presence of acid, fat, protein breakdown products, hyperosmotic or hypo-osmotic fluids, or any irritating factor in the upper small intestine causes release of secretin which opposes stomach secretion. They also cause secretion of P, vasoactive intestinal polypeptide and somatostatin, which also inhibit gastric secretion → Ghrelin: Hormone secreted mainly from the stomach into the circulation. It stimulates growth-hormone release, appetite and food intake. Useful for treatment of weight loss and eating disorders. It improves cardiovascular function. → Arcuate nucleus of hypothalamus is the main target of ghrelin and leptin (secreted by adipose). Ghrelin is orexigenic (appetite stimulant) and leptin is anorexigenic (caused anorexia). At the nucleus ghrelin stimulates neurons expressing neuropeptide Y and agouti-related peptide and leptin suppresses them → Neuropeptide Y is released in response to ghrelin and it stimulates appetite and increases body weight. → Gastric bypass: To treat severe obesity. Reduce the space for food in the gastric cavity and thus reduce total caloric intake. The mean plasma ghrelin concentration decreases significantly after gastric bypass. Pancreatic and Bile Secretion PowerPoint (MP), Book Chapter 65 → Pancreas lies parallel to and beneath the stomach. Large compound gland. Most of its internal structure is similar to that of the salivary glands. → Pancreatic digestive enzymes are secreted by pancreatic acini, while large volumes of sodium bicarbonate solution are secreted by small ductules and larger ducts leading from the acini. → Combined product of enzymes and sodium bicarbonate then flows through a long pancreatic duct that normally joins the hepatic duct immediately before it empties into the duodenum through the papilla of Vater, surrounded by the sphincter of Oddi → Pancreatic juice is secreted most abundantly in response to the presence of chyme in the upper portions of the small intestine. Characteristics of pancreatic juice are determined to some extent by the types of food in the chyme. 14 MMSA SCOME Notes Database Elsa Cassar → Pancreas also secretes insulin, but it is not secreted by the same pancreatic tissue that secretes intestinal pancreatic juice. Insulin is instead secreted directly into the blood by the islets of Langerhans → Sphincter of Oddi is a very small but powerful ring of muscle found at the junction where the tube that carries bile and the tube that carries pancreatic juice meet. It regulates the flow of these substances into the duodenum. → After meals, especially rich/fatty ones, the gallbladder contracts to release bile. The sphincter of Oddi relaxes to allow flow of bile into the duodenum. → Any abnormality of the muscle affecting its proper relaxation causes bile and pancreatic secretions to accumulate and flow back until it becomes stagnant, leading to forceful contraction of the distended tube. This causes severe cramping and right upper abdominal pain. → Odditis is inflammation of the sphincter of Oddi → Acidification of the duodenal lumen is the most effective stimulus for the release of secretin from S cells, which begins when the pH drops below the value of 4.5 and reaches a maximum at pH 3. Secretin promotes secretion of aqueous NaHCO3 solution from ductal cells that then increases pH. Hence, secretin is nature’s antacid → Since the mucosa of the small intestine cannot withstand the digestive action of acid gastric juice, this is an essential protective mechanism to prevent the development of duodenal ulcers. → HCl + NaHCO3 → NaCl + H2CO3 → The latter is carbonic acid, which immediately dissociates into CO2 (absorbed into the blood and expired in the lungs) and water. → Pancreatic secretion contains multiple enzymes and large quantities of bicarbonate ions (for neutralisation). → The pancreatic enzyme for digesting carbohydrates is pancreatic amylase. It hydrolyses starches, glycogen and most other carbohydrates (except cellulose) into mostly disaccharides and a few trisaccharides → The main pancreatic enzymes for fat digestion are pancreatic lipase (neutral fat into fatty acids and monoglycerides); cholesterol esterase (hydrolysis of cholesterol esters) and phospholipase (splits fatty acids from phospholipids). → Most important pancreatic enzymes for digesting proteins are trypsin, chymotrypsin and carboxy-polypeptidase. By far the most abundant is trypsin. → Trypsin and chymotrypsin split whole proteins into peptides of various sizes. → Carboxy-polypeptidase splits some peptides into individual amino acids → All three above are released as zymogens that become activated in the intestinal tract. Trypsinogen is activated by enterokinase (secreted by intestinal mucosa when chyme comes into contact with it). Trypsin can then activate more trypsinogen, as well as chymotrypsinogen and procarboxypolypeptidase → The same cells that secrete proteolytic enzymes into the acini also secrete trypsin inhibitor. It is formed in the cytoplasm of the glandular cells and prevents activation of 15 MMSA SCOME Notes Database Elsa Cassar trypsin both inside the secretory cells as well as in the acini and ducts of the pancreas, to avoid them digesting the pancreas. → When the pancreas becomes severely damaged or a duct is blocked, large quantities of pancreatic secretion sometimes pools in the damaged areas. The effect of trypsin inhibitor is often overwhelmed, and the pancreas is digested in a few hours, causing acute pancreatitis. It is sometimes lethal due to circulatory shock. If it is not lethal, it usually leads to a subsequent lifetime of pancreatic insufficiency. → While pancreatic enzymes are secreted entirely by the acini of the pancreatic glands, the other two important components of pancreatic juice (bicarbonate ions and water) are secreted mainly by the epithelial cells of the ductules and ducts that lead from the acini. → Bicarbonate ion concentration can rise up to 145 mEq/L (five times as in the plasma), providing a large quantity of alkali in the pancreatic juice that serves to neutralise the HCl. → Steps for secreting sodium bicarbonate into the pancreatic ductules and ducts are as follows: 1. CO2 enters from the blood into the cell. Under the influence of carbonic anhydrase, it combines with water to form carbonic acid, which dissociates into bicarbonate and hydrogen ions. 2. Additional bicarbonate ions enter the cell by co-transport with sodium ions. 3. Bicarbonate ions are then exchanged for Cl- at the luminal border by secondary active transport. The chloride that enters is recycled back into the lumen by special chloride channels 4. Hydrogen ions formed by dissociated are exchanged for Na+ at the basolateral membrane. Na+ enters by co-transport with bicarbonate and are then transported across the luminal border into the lumen. The negative voltage of the lumen also pulls Na+ across the tight junctions between the cells 5. Overall movement creates an osmotic pressure gradient that causes osmosis of water also into the pancreatic duct. → Secretin directly stimulates epithelial cells to secrete bicarbonate ions into the ductal lumen, with water following to maintain osmotic equilibrium. → Secretin increases cAMP in the ductular cells, thereby opening CFTR Cl- channels to exchange Cl- for bicarbonate. Hence, the bicarbonate secretory process is dependent on CFTR, thus defects in pancreatic function are seen in cystic fibrosis, where CFTR is mutated. → Thymosin-alpha1 is being considered as therapy for cystic fibrosis since it promotes an increase in residual activity of mutant CFTR channels and promotes proper trafficking of mutant CFTR to the plasma membrane. → Brunner’s glands: Extensive array of compound mucous glands found in the wall of the first few centimetres of the duodenum, mainly between pylorus and papilla of Vater. 16 MMSA SCOME Notes Database Elsa Cassar Secrete large amounts of alkaline mucus in response to tactile or irritating stimuli on duodenal mucosa, to vagal stimulation and to GI hormones (especially secretin. → The function of this alkaline mucus is to protect the duodenal wall from digestion by the highly acidic gastric juice and to neutralise the HCl. → They also secrete urogastrone, which inhibits parietal and chief cells of the stomach from secreting acid and their digestive juices. → Brunner’s glands are inhibited by sympathetic stimulation. Hence, such stimulation in very excitable persons is likely to leave this area of the duodenum unprotected, making it the site of peptic ulcers in 50% of persons with ulcers. → Cholecystokinin is the product of I cells, found in the small intestinal epithelium. They release CCK into the interstitial space in response to free fatty acids and certain amino acids in the lumen. Release of CCK is also regulated by CCK-released factor (secreted by paracrine cells within the epithelium) and by monitor peptide (released by pancreatic acinar cells). These two hormones are also released in response to neural input, particularly important in the cephalic and gastric phases. → CCK functions in causing secretion of more pancreatic digestive enzymes by the acinar cells. It does this in two ways: 1. It is a classic hormone that travels through the bloodstream to encounter acinar cell CCK1 receptors 2. It stimulates neural reflex pathways that impinge on the pancreas. Vagal afferent nerve endings are responsive to CCK, activating a vagovagal reflex that enhances acinar cell secretion by activation of pancreatic enteric neurons and release of NTs e.g. ACh, gastrin-releasing peptide and VIP. → Pancreatic secretion, as with gastric secretion, occurs in three phases: 1. Cephalic phase: Same nervous signals from the brain that cause secretion in the stomach also cause ACh release by vagal nerve endings in the pancreas. This causes moderate amounts of enzymes to be secreted into the pancreatic acini, accounting for about 20% of the total secretion pancreatic enzymes. However, little of the secretion flows immediately through the pancreatic ducts into the intestine. 2. Gastric phase: Nervous stimulation continues, accounting for 5-10% of pancreatic enzyme release. However, only small amounts reach the duodenum because of continued lack of significant fluid secretion 3. Intestinal phase: After chyme leaves the stomach, pancreatic secretion becomes copious, mainly in response to secretin. → Three stimuli are important in causing pancreatic secretion: 1. Acetylcholine: Released from the parasympathetic vagus nerve endings and from other cholinergic nerves in the enteric nervous system 2. Cholecystokinin: Secreted by the duodenal and upper jejunal mucosa when food enters the small intestine 17 MMSA SCOME Notes Database Elsa Cassar 3. Secretin: Secreted by the duodenal and jejunal mucosa when highly acidic food enters the small intestine → The first two, ACh and CCK, stimulate the acinar cells of the pancreas, causing production of large quantities of digestive enzymes but relatively small quantities of water and electrolytes. Secretin then stimulates the release of large quantities of water solution of sodium bicarbonate, thus washing the enzymes into the duodenum. → Secretin: Present in an inactive form (prosecretin) in S cells in the mucosa of the duodenum and jejunum. When acid chyme with pH less than 5 enters the duodenum, it causes release and activation of secretion, which is then absorbed into the blood. This causes the pancreas to secrete large quantities of fluid containing a high concentration of bicarbonate and low concentration of chloride. This mechanism is important to prevent ulcer formation. → Bile secretion: Between 600 to 1000 ml/day. Important role in fat digestion and absorption since bile acids emulsify large fat particles into minute ones, increasing surface for enzyme attack, as well as aiding in absorption through the intestinal mucosal membrane. Bile also serves as a means for excretion of several important waste products from the blood, particularly bilirubin and cholesterol. → Bile is secreting in two stages by the liver: 1. Initial portion secreted by hepatocytes. Contains large amounts of bile acids, cholesterol and other organic constituents. Secreted into minute bile canaliculi that originate between hepatic cells. 2. Next, bile flows in the canaliculi toward the interlobular septa, where the canaliculi empty into terminal bile ducts and then into larger ducts, finally reaching the hepatic duct and common bile duct. From these ducts, the bile either empties directly into the duodenum or is diverted through the cystic duct into the gallbladder. → In its course through the bile ducts, a water solution of sodium and bicarbonate ions secreted by epithelial cells is added to the initial bile. Increases the total quantity of bile by as much as 100%. This secretion is stimulated especially by secretin, for neutralisation. → Bile is secreted by the liver but stored by the gallbladder. Gallbladder absorption is caused by active transport of sodium, followed by secondary absorption of Cl -, H2O and most other diffusible constituents. → When food is in the upper GI, the gallbladder starts to empty, especially when fatty foods reach the duodenum (about 30 minutes after a meal). Mechanism of emptying is rhythmical contractions of the gallbladder wall. Also requires simultaneous relaxation of the sphincter of Oddi, which guards the exit of the common bile duct. → CCK is the most potent stimulus for gallbladder contractions. Also stimulated less strongly by ACh-secreting nerve fibres from both the vagi and the intestinal enteric nervous system. → Precursor of bile salts is cholesterol, either from the diet or synthesised by the liver during fat metabolism. Cholesterol is first converted to cholic acid or to chenodeoxycholic acid. 18 MMSA SCOME Notes Database Elsa Cassar These combine with glycine or taurine to form bile acids. The salts of these acids are then secreted in the bile. → Bile salts have two important actions: 1. Detergent/emulsifying action: Decreases surface tension and allows agitation 2. Absorption: Form small physical complexes called micelles Liver Function PowerPoint, Chapter 71 (eBook) → Functions of the liver: Filtration and storage of blood; metabolism of carbohydrates, proteins, fats, hormones and foreign chemicals; Formation of bile; Storage of vitamins and iron; Formation of coagulation factors → Anatomy: Largest organ in the body. o Basic functional unit is the liver lobule, constructed of a central vein that empties into the hepatic veins and then into the vena cava. o Composed of cellular plates that radiate from the central vein. Each is usually two cells thick and between the adjacent cells lie bile canaliculi that empty into bile ducts. o In the septa there are small portal venules that receive their blood mainly from the venous outflow of the GI tract by the portal vein. From these venules blood flows into hepatic sinusoids lying between the hepatic plates and then into the central vein. o Hepatic arterioles are also present in the interlobular septa. They supply arterial blood to the septal tissues and many empty directly into the hepatic sinusoids. o Venous sinusoids are lined by two other cell types, the typical endothelial cells and the large Kupffer cells (also called reticuloendothelial cells) that are resident macrophages that phagocyte bacteria and other foreign matter from the hepatic sinus blood o Lying between endothelial cells and hepatic cells are narrow tissue spaces called spaces of Disse (or perisinusoidal spaces) that connect with lymph vessels. → Cirrhosis is when liver parenchymal cells are destroyed and replaced by fibrous tissue that eventually contracts around the blood vessels. This causes impediment of the flow of portal blood through the liver. Results from chronic alcoholism or excess fat accumulation in the liver and subsequent liver inflammation (non-alcoholic steatohepatitis) → Non-alcoholic fatty liver disease: Less severe form of fat accumulation and inflammation of the liver. Associated with obesity and type II diabetes. → Cirrhosis can also be caused by ingestion of poisons, viral diseases, obstruction of the bile ducts and infectious processes in the bile ducts. → The portal system is also occasionally blocked by a large clot that develops in the portal vein or its major branches. The movement of blood is impeded, resulting in portal 19 MMSA SCOME Notes Database Elsa Cassar hypertension, with capillary pressure in intestinal wall increasing to 15-20mmHg above normal. The patient may die within a few hours due to excess loss of fluid from the capillaries into the lumens and walls of the intestines. → The liver functions as a blood reservoir. Its normal blood volume is 450 millilitres (almost 10% of total) but can store up to 30% if there is high pressure in the right atrium, especially in cases of cardiac failure with peripheral congestion. → The liver has a very high lymph flow, since the pores in the sinusoids are very permeably, allowing passage of both fluids and proteins into the spaces of Disse. → High hepatic vascular pressures (only 3-7mmHg above normal) can cause fluid transudation into the abdominal cavity. This fluid is almost pure plasma. At vena caval pressures of 10-15mmHg, hepatic lymph flow increases to as much as 20 times as normal causing ascites. → Blockage of portal flow through the liver also causes high capillary pressures in the entire portal vascular system of the GI tract, resulting in oedema of the gut wall and transduction of fluid into the abdominal cavity, also causing ascites. → Generalised cellular deterioration: As shock becomes severe, signs of generalised cellular deterioration occur throughout the body. The liver is especially affected, due to the lack of enough nutrients to support the normally high rate of metabolism, as well as due to the extreme exposure of the liver cells to vascular toxin or other abnormal metabolic factors occurring in shock. → Regeneration: Possible after partial hepatectomy or acute liver injury, as long as it is uncomplicated by viral infection of inflammation. Remarkably rapid. Hepatocytes replicate one or twice until the original size and volume is achieved, and the cells then revert back to quiescence. → Hepatocyte growth factor appears to be important in causing liver cell division and growth. HGF is produced by mesenchymal cells in the liver and in other tissues, but not by hepatocytes. Blood levels rise more than 20-fold after hepatectomy. Other growth factors (epidermal growth factor) and cytokines (tumour necrosis factor, IL-6) may also be involved. → Trans-forming growth factor-beta is a cytokine secreted by hepatic cells that inhibits liver cell proliferation and has been suggested to be the main terminator of liver regeneration. → Hepatic macrophage system cleanses the blood, since blood flowing through the intestinal capillaries picks up many bacteria from the intestines. Kupffer cells line hepatic venous sinuses to phagocyte bacteria. → Carbohydrate metabolism in the liver: Storage of large amounts of glycogen; Conversion of galactose and fructose to glucose; Gluconeogenesis; Formation of many chemical compounds from intermediate products of carbohydrate metabolism. → The liver is especially important for maintaining a normal blood glucose concentration. → Fat metabolism in the liver: Oxidation of fatty acids to supply energy for other body functions; Synthesis of large quantities of cholesterol, phospholipids and most lipoproteins; Synthesis of fat from proteins and carbohydrates. 20 MMSA SCOME Notes Database Elsa Cassar → To derive energy from neutral fats: Fat is split into glycerol and fatty acids. Fatty acids are split by beta-oxidation into two-carbon acetyl radicals that form acetyl coA, which can then enter the citric acid cycle and be oxidised to liberate energy. → Beta-oxidation can take place in all cells of the body, but it occurs especially rapidly in the hepatic cells. The liver cannot use all the acetyl CoA formed, thus it converts it into acetoacetic acid that passes into the extracellular fluid and is transported throughout the body to be absorbed by other tissues. These tissues reconvert the acetoacetic acid into acetyl CoA and then oxidise it in the usual manner. → About 80% of the cholesterol synthesised in the liver is converted to bile salts which are then secreted into the bile. The remainder is transported in the lipoproteins and carried by the blood to the tissue cells of the body. Phospholipids are likewise synthesised in the liver and transported principally in the lipoproteins. → Protein metabolism in the liver: Deamination of amino acids, formation of urea, formation of plasma proteins and interconversions of various amino acids and synthesis of other compounds from amino acids. → Deamination of amino acids is required before they can be used for energy or converted to carbohydrates or fats. → Formation of urea removes ammonia from the body fluids. Large amounts of ammonia are formed by the deamination process and additional amounts are formed in the guy by bacteria and absorbed into the blood. Hepatic coma occurs from high plasma ammonia concentration. → All plasma proteins except gamma globulins are formed by hepatic cells. Gamma globulins are antibodies formed by plasma cells in lymph tissue of the body. → Plasma protein depletion causes rapid mitosis of hepatic cells and growth of liver to a larger size for rapid output of plasma proteins. Chronic liver disease causes plasma proteins to fall to very low levels, causing generalised oedema and ascites. → Liver is a storage site for vitamins, mostly vitamin A, D and B12. → The liver stores ferritin, which is a combination of iron and apoferritin. The ferritin releases the iron when body fluids reach low iron levels. → Coagulation substances such as fibrinogen, prothrombin, accelerator globulin, factor VII and other important factors are formed in the liver. Vitamin K is required for the formation of most of these. → The liver carries out detoxification and excretion of drugs and hormones. It also excretes calcium into the bile. → Bilirubin is one of the substances excreted in bile, a major end product of haemoglobin degradation. Valuable tool for diagnosing other haemolytic blood diseases and various types of liver diseases. → When RBCs have lived out their life span, their cell membranes rupture. The haemoglobin is phagocytised by the reticuloendothelial system (tissue macrophages) throughout the body. It is split into globin and heme. The heme ring is opened to give free iron (transported in body by transferrin) and a straight chain of four pyrrole nuclei. 21 MMSA SCOME Notes Database Elsa Cassar → The pyrrole is converted to biliverdin, then to free bilirubin (unconjugated bilirubin) which is gradually released from the macrophages into the plasma. This combines strongly with albumin and is transported to the liver. There is conjugated with glucuronic acid/sulfate/other substances to form bilirubin glucuronide, bilirubin sulfate or others. In these forms, it is excreted from the hepatocytes actively into the bile canaliculi and then into the intestines. → When in the intestine, half of the bilirubin is converted by bacteria into urobilinogen, which is highly soluble. Some of it is reabsorbed back into the blood but most is re- excreted by the liver back into the gut and a small percentage is excreted by the kidneys into the urine. → After exposure to air in the urine, urobilinogen becomes urobilin → In the faeces, it becomes altered and oxidised to stercobilin → Jaundice: Yellowish tint of body tissues. Usually caused by large quantities of bilirubin in extracellular fluids. Can rise from 0.5mg/dl to up to 40mg/dl, in which case much of it becomes the conjugated type. Skin tints at levels above 1.5mg/dl → Common causes are increased destruction of RBCs or obstruction of bile ducts or damage to liver cells. These are haemolytic jaundice and obstructive jaundice → Haemolytic jaundice: Haemolysis of RBCs. Hepatic cells cannot excrete bilirubin as rapidly as it is formed. Free bilirubin plasma concentrations rise, as well as the rate of formation of urobilinogen. → Obstructive jaundice: Obstruction of bil ducts (gallstone or cancer blocks common bile duct) or by damage to hepatic cells (hepatitis). Rate of bilirubin formation is normal, but the bilirubin formed cannot pass from the blood into the intestines. The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual way, but is then returned to the blood, probably due to rupture of the congested bile canaliculi and direct emptying of the bile into the lymph leaving the liver. → Diagnostic differences: o In haemolytic jaundice, bilirubin is mostly unconjugated, while in obstructive it is conjugated. This can be tested by the van de Bergh reaction. o In total obstructive jaundice, no urobilinogen reaches the intestine and therefore urobilinogen in the urine is completely negative. Also, stools become clay coloured owing to a lack of stercobilin and other bile pigments o In severe obstructive jaundice, significant quantities of conjugated bilirubin appear in the urine, demonstrated by shaking the urine and observing the foam, which turns an intense yellow. Digestion PowerPoint, Chapter 66 → Hydrolysis: 22 MMSA SCOME Notes Database Elsa Cassar o Of carbohydrates: Almost all carbohydrates are polysaccharides or disaccharides, which are combinations of monosaccharides bound by condensation. This phenomenon means that an H+ has been removed from one monosaccharide and an OH- from the other. Enzymes separate the monosaccharides by reacting the polysaccharides with water o Of fats: Hydrolysis of triglycerides consists of fat-digesting enzymes returning three molecules of water to the triglyceride molecule o Of proteins: At each peptide linkage, an OH- and H+ have been removed. A. Carbohydrates → Only three major sources of carbohydrates exist in the diet, sucrose, lactose and starches. → Digestion begins in the mouth, where it is mixed with saliva that contains ptyalin (alpha- amylase) which hydrolyses starch into maltose and other small polymers of glucose. → Starch digestion continues in the stomach for as long as an hour before it becomes too mixed with the stomach secretions. Then, activity is blocked by the acid. → Pancreatic amylase is almost identical to salivary amylase but is much more powerful, converting carbohydrates into maltose and/or other small glucose polymers → Enterocytes lining the villi of the small intestine contain four enzymes (lactase, sucrase, maltase and alpha-dextranase), which are capable of splitting disaccharides into monosaccharides. All are water soluble and are absorbed immediately into the portal blood. B. Proteins → Proteins are long chains of amino acids bound by peptide linkages. → Pepsin is an important peptic enzyme in the stomach, most active at pH 2 to 3, and inactive about pH 5. Gastric glands secrete a large quantity of HCl by parietal (oxyntic) cells, at a pH of 0.8. → Collagen is a major constituent of intercellular connective tissue of meats. Its digestion is one of the important features of pepsin digestion since it is affected little by other digestive enzymes. This is since, for the digestive enzymes to penetrate meats and digest the other meat proteins, it is necessary that the collagen fibres are digested. → Most protein digestion occurs in the upper small intestine under the influence of proteolytic enzymes from pancreatic secretion. → Major proteolytic pancreatic enzymes are trypsin, chymotrypsin, carboxy-polypeptidase and elastase. The prior two split protein into small polypeptides. Carboxy-polypeptidase cleaves individual amino acids from the carboxyl ends. Elastase digests elastin fibres the partially holds meat together. → Only a small percent is digested into amino acids. Most remain as dipeptides and tripeptides. → Last digestive stage is achieved by enterocytes which have microvilli on their surface. These contain multiple peptidases, including aminopolypeptidase and dipeptidases. These split the remaining polypeptides into tripeptides, dipeptides and a few amino acids. 23 MMSA SCOME Notes Database Elsa Cassar → Inside the cytosol are multiple other peptidases specific for the remaining types of linkages, to form single amino acids. C. Fats → A small amount of fats is digested in the stomach by lingual lipase secreted by lingual glands in the mouth and swallowed with the saliva. → First step is emulsification by bile acids and lecithin, where fat globules are broken into small sizes so that water-soluble digestive enzymes can act on the globule surfaces. → Polar parts of lecithin and bile salts are highly soluble in water, while most of the remaining portions are highly soluble in fat. → Lipase enzymes are water-soluble compounds and can attack the fat globules only on their surfaces → Pancreatic lipase is the most important enzyme for digestion of triglycerides. Enteric lipase also exists but it is usually not needed since the pancreatic lipase is very efficient → End products of fat digestion are free fatty acids → Bile salts form micelles that transport the monoglycerides and free fatty acids to the brush borders of the intestinal epithelial cells. → Most cholesterol in the diet is in the form of cholesterol esters, combinations of free cholesterol and one molecule of fatty acid. Phospholipids also contain fatty acid within their molecules. Both the cholesterol esters and the phospholipids are hydrolysed by two other lipases in the pancreatic secretion that free the fatty acids, cholesterol ester hydrolase and phospholipase A2 respectively. Bile salt micelles play the same role in transporting them. → Valvulae conniventes: Aka Folds of Kerckring. Folds in the small intestinal mucosa that increase the surface area of the mucosa about threefold. Extend circularly most of the way around the intestine and are especially well developed in the duodenum and jejunum → Villi are present on the epithelial surface of the small intestine all the way down to the ileocaecal valve. Present very close to one another in the upper small intestine but less profuse in the distal small intestine. → Each villus is made up of many epithelial cells, each of which has as many as 1000 microvilli → The entire small intestine makes up the surface area of a tennis court. → Pinocytic vesicles: Pinched-off portions of infolded enterocyte membrane forming vesicles of absorbed fluids that have been entrapped. → Actin filaments extend from the epithelial cell body to each microvillus for rhythmic contraction. → Water is transported by osmosis, both paracellularly and transcellularly. It can be transported in opposite direction, depending on the osmolarity of the food ingested. → Cholera toxin: Usual source is undercooked seafood. It produces cAMP, which leads to secretion of water, sodium, potassium and bicarbonate into the lumen of the small intestine and rapid dehydration. Carried by Vibrio cholerae which attaches to the epithelial cells of the small intestine. The toxin enters the cell and prevents them from 24 MMSA SCOME Notes Database Elsa Cassar down-regulating secretion of water and electrolytes, causing watery diarrhoea. Shock and death occur due to fluid loss in the circulatory system, unless the fluid can be replaced. → Hyponatraemia: Most common electrolyte abnormality in hospitalised patients. Increases the likelihood of hospital death. → Cerebral oedema: Severe hyponatraemia causes water entry into the brain. Build-up of water can make the brain expand, which can result in brain damage. → Aldosterone: Secreted by cortices of adrenals. Increases activation and transport mechanisms for all aspects of sodium absorption. Increased sodium absorption causes secondary increases in absorption of chloride, water and some others. → Bicarbonate is secreted into the upper small intestine by the pancreas and must be reabsorbed. Hydrogen ions react with bicarbonate to form carbonic acid that dissociates to water and CO2. The water remains as part of the chyme and the CO2 is absorbed into the blood and expired. → The ileum and large intestine are capable of secreting bicarbonate ions in exchange for absorption of chloride. This is important to neutralise the acid products formed by bacteria in the large intestine → Calcium ions are actively absorbed into the blood, especially from the duodenum. The amount of calcium ion absorption is exactly controlled to supply the daily calcium need → Parathyroid hormones and vitamin D are important in this regulation. Parathyroid hormones activated vitamin D which then greatly enhances Ca2+ absorption. → Ca2+ is absorbed from the duodenum and jejunum by both a Ca 2+-regulated and hormonally regulated transcellular route and by a passive paracellular route. → Iron ions are also actively absorbed from the small intestine. → Anaemia: Haemoglobin below 12g/dl in women and 13g/dl in men. Treated by oral iron supplementation. Causes easy fatigue, loss of energy, rapid heartbeat, shortness of breath, headache, difficulty concentrating, dizziness, pale skin, leg cramps and insomnia. → People at risk of anaemia are infants who do not receive enough iron in the diet; children during leaps of growth; menstruation or menstrual problems; pregnant women; chemotherapy; haemorrhaging ulcers → Ascorbate and citrate increase iron uptake by acting as weak chelators to help to solubilize the metal in the duodenum → Potassium, magnesium and phosphate are also actively absorbed. The monovalent ions are absorbed with ease and in great quantities while bivalent ions are absorbed in small amounts. → Glucose is absorbed in co-transport with sodium, occurring in two stages- Active transport of sodium ions through the basolateral membranes of the intestinal epithelial cells. Decrease in sedum inside the cells causes sodium from the intestinal lumen to move through the brush border of the epithelial cells to the interior by secondary active transport together with another substance such as glucose. Galactose is transported in the same way. 25 MMSA SCOME Notes Database Elsa Cassar → Fructose is not absorbed by sodium co-transport. It is transported by facilitated diffusion. It is converted into glucose within the cell and is transport in the form of glucose the rest of the way into the blood. → Peptides and amino acids are also transported by co-transport with sodium. → Micelles penetrate into the recesses among the microvilli. Here, the monoglycerides and fatty acids diffuse out of the micelles and into the interior of the epithelial cells. The bile micelles remain in the chyme to function again and again → Fatty acids and monoglycerides are taken up by the cell’s smooth ER where they form new triglycerides that are released in the form of chylomicrons to glow up through the thoracic lymph duct and empty into circulating blood. → Small quantities of short- and medium-chain fatty acids are absorbed directly into the portal blood rather than being converted into triglycerides and absorbed by lymphatics. This is since they are more water soluble. → Most water and electrolytes left in the chyme after passing through the ileocaecal valve are absorbed by the colon. Most of this absorption occurs in the proximal half of the colon, giving this portion the name absorbing colon. → The distal colon functions principally for faeces storage and is thus called storage colon → The colon has a high capability for active absorption of sodium. The electrical potential gradient created causes chloride absorption as well. → The tight junctions between the epithelial cells of the large intestinal epithelium are much tighter than those of the small intestine to prevent back-diffusion. → It also secretes bicarbonate ions while absorbing an equal number of chloride ions in exchange. This is to help neutralise the acidic end products of bacterial action. → Toxins from cholera or certain other bacterial infections can cause the crypts in the terminal ileum and large intestine to secrete fluids, leading to diarrhoea → Brown colour of faces is caused by stercobilin and urobilin. Drug Metabolism PowerPoint (JM) → The pharmokinetic process consists of: o Absorption from the GI tract and other sites of administration into the blood o Distribution: Between the blood and sites of action o Metabolism: Between the blood and liver o Excretion: From the kidneys → The above is ADME and it determines how much of an administered dose gets to its sites of action → First pass effect: Phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. A fraction is lost during the process of absorption, generally related to the liver and gut wall. 26 MMSA SCOME Notes Database Elsa Cassar → Biotransformation: Chemical changes to a drug into a metabolite that can be easily eliminated from the body, by making it more water-soluble. The liver is primarily responsible for this task, but it can also occur in the plasma, kidneys, lungs and intestinal mucosa. → Lipophilic drugs tend to be metabolised to a greater extent than hydrophilic drugs. → DMEs are drug metabolising enzymes: o Extrahepatic microsomal enzymes for oxidation and conjugation o Hepatic microsomal enzymes for oxidation and conjugation o Hepatic non-microsomal enzymes for acetylation, sulphation, GSH, alcohol/aldehyde dehydrogenase, hydrolysis, oxidation, reduction → DMEs are found in almost all organs, but especially the liver and the intestine. → They are found in the cytosol, endoplasmic reticulum and mitochondrial inner plasma membrane in cells. → CYP families: Cytochrome P450. Proteins of the superfamily containing heme as a cofactor. Most of DMEs are in CYP 1, 2 and 3 families. Frequently, two or more enzymes can catalyse the same type of oxidation, indicating redundant and broad substrate specificity. → CYP3A4 is very common to the metabolism of many drugs. Its presence in the GI tract is responsible for poor oral availability of many drugs. → Cytochromes vary in the structure of the heme and in its binding to apoprotein. Cytochromes of the c type contain a modified iron protoporphyrin IX known as heme c. in heme c, the 2 vinyl side chains are covalently bonded to cystine sulfhydryl residues of the apoprotein. Only cytochromes of the c type contain covalently bound heme. Heme a is also a modified iron protoporphyrin IX. Heme a is found in cytochromes of the a-type and in the chlorophyll of green plants. → Nomenclature: Family indicated by number, subfamily by letter. If there is more than one subfamily, an additional number is added. E.g. CYP1A2. Note that enzyme genes are always written in italics. → Drugs usually undergo one or both of the following types of chemical reactions in the liver: o Oxidation, hydrolysis or reduction: To become more soluble o Conjugation: Usually with glucose → Drugs that are administered orally normally travel first to the liver prior to entering the general circulation. This first-pass metabolism may cause significant deterioration (metabolism) of the active drug, thus rendering the drug inactive. → Other non-microsomal reactions: o Hydrolysis in the plasma by esterases o Alcohol and aldehyde dehydrogenase in the cytosolic fraction of the liver o Monoamine oxidase in the mitochondria o Xanthene oxidase o Enzymes for particular drugs 27 MMSA SCOME Notes Database Elsa Cassar → Factors that affect biotransformation: o Age: Children have immature metabolising enzyme systems. Biotransformation is reduced in older persons o Sex: Women are more sensitive to ethanol o Clinical or physiological condition: Such as liver, cardiovascular or renal problems o Environmental factors: Smoking and alcohol o Genetics: Fast and slow metabolisers o Species differences o Induction and inhibition: Two major types of CYP inducers: (1) Phenobarbital is a prototype of one group, which enhances metabolism of wide variety of substrates by causing proliferation of SER and CYP in liver cells. (2) Polycyclic aromatic hydrocarbons are a second type of inducer. Induction appears to be an environmental adaptive response of an organism. Orphan nuclear receptors are regulators of drug metabolising gene expression → Inhibitors: Prolongs action of drugs or inhibits action of those biotransformed to active agents → Inducers: Shorten the action of drugs or increase effects of those biotransformed to active agents → Blockers: Act on non-microsomal enzymes → Non-nitrogenous substances that affect drug metabolism include grapefruit juice, herbal products and isosafrole/safrole, which is found in root beer and perfume → Grape juice elevates the plasma peak drug concentration but not the elimination half time. It reduces the metabolite to parent drug ‘area under the chart’ ratio. Effects last around 4 hours, thus requiring new enzyme synthesis. The effect is cumulative and highly variable amount individuals. → Mutations can occur in these genes, causing poor metabolisers (non-functional product), intermediate metabolisers (reduced affinity or stability) and ultra-rapid metabolisers (gene amplification) → Key receptors involved in metabolism are pregnane X receptor (PXR) and constitutive androstane receptor (CAR) → PXR: One of nuclear receptor (NR) family of ligand-activated transcription factors. Named on basis of activation by pregnanes. Cloned due to homology with other nuclear receptors. Highly active in the liver and intestine. Binds as heterodimer with retinoic acid receptor (RXR) → CAR: Highly expressed in the liver and intestine. Sequestered in the cytoplasm. Co-factor complex required for activation. Anchored by PPAR-binding protein. Binds response elements as RXR heterodimer. High basal transcriptional activity without ligand. Activated by xenobiotics. 28 MMSA SCOME Notes Database Elsa Cassar Gastrointestinal Motility PowerPoint (MP), Guyton → Parasympathetic stimulation causes increased peristalsis and relaxes sphincters, while sympathetic stimulation inhibits peristalsis and increases the tone of the sphincters. Net result of sympathetic stimulation is greatly slowed propulsion of food through the tract and sometimes decreased secretion. → Peristalsis reflex: Complex pattern of contractions and relaxations of the GIT wall. Also called myenteric reflex since it does not occur in the absence of the myenteric plexus → Peristatic reflex plus the downstream direction of the movement of the peristalsis is called the law of the gut → Peristalsis: Propagating wave produced by simultaneous contraction of circular musculature and relaxation of longitudinal musculature and simultaneous relaxation of circular musculature and contraction of longitudinal muscular (downstream) → Physiological ileus: Condition characterised by the absence of motility in the small and large intestines. Functional condition programmed by the ENS and caused by the activity of inhibitory neurons that determines a temporary absence of motility. → Paralytic ileus: Condition characterised by prolonged absence of motility. Caused by a state of uninterrupted activity of inhibitory neurons that prevents any motility. → Auscultation for bowel sounds should hear 5-30 times/minute → Absence of peristalsis is characteristic of paralytic intestinal occlusion, linked to various conditions but especially to surgery. → Motilin: Induces intense contractions that propagate caudally. → Gastric motility in the fasted state is a cyclical phenomenon called the migrating motor complex. In a normal MMC, there are four phases: o Phase 1: Quiescent period with virtually no contractions o Phase 2: Intermittent, irregular low-amplitude contractions o Phase 3: Short bursts of regular high-amplitude contractions. Periodically occur every 90-120 minutes in humans o Phase 4: Short transition period back to the quiescence of phase 1 → Plasma motilin level is highly associated with the appearance of gastric phase 3 in humans → These are also called starvation contractions → In the stomach, the lower oesophageal sphincter contracts while the pylorus and ileocecal valve are completely open. Both the gastric and pancreatic secretions are stimulation → In the duodenum, peristaltic activity migrates through the duodenum, jejunum and ileum. The luminal GIT content is propelled caudally. Undigested food residues are cleared out and bacterial colonisation is reduced. → Motilin: Induces intense contractions (phase 3) that propagate caudally. In humans, it is encoded by MLN gene. Secreted by endocrine M cells that are numerous in crypts of the small intestine (especially duodenum and jejunum). Released into the general circulation in humans about 100-minute intervals during the inter-digestive state. 29 MMSA SCOME Notes Database Elsa Cassar → Ileocecal valve protrudes into the lumen of the cecum and therefore is forcefully closed when excess pressure builds in the cecum and tries to push caecal contents backwards against the valve lips. → Wall of the ileum for several centimetres immediately upstream from the ileocecal valve has a thickened circular muscle called the ileocecal sphincter that normally remains mildly constricted and slows emptying of ileal contents into the cecum. → Ileocecal valve and sphincter prevent the passage of faecal matter back from the colon into the small intestine, since this reflux is toxic → The chyme stops at the level of the IC valve for several hours, prolonging the absorption of nutrients. The valve then opens when the subject ingests the next meal → The meal triggers the gastro-ileal reflex, which intensifies peristalsis in the ileum opens the ileocecal valve and sphincter and promotes passage of chyme into the colon → Gastrin, released from the gastric mucosa, stimulates peristalsis in the ileum and the relaxation of the IC valve. → Gastro-ileal reflex is one of the three extrinsic reflexes of the GI tract. The other two are the gastrocolic reflex and the enterogastric reflex. → The gastro-ileal reflex is stimulated by the presence of food in the stomach and by gastric peristalsis. Initiation of the reflex causes peristalsis in the ileum and the opening of the IC valve. This in turn stimulates colonic peristalsis and an urge to defecate. → IC sphincter and peristalsis intensity are controlled significantly by reflexes from the cecum. → Distension of the cecum causes contraction of the IC sphincter and ileal peristalsis inhibition, greatly delaying emptying of additional chyme into the cecum. → Also, irritants in the cecum delay emptying, such as inflamed appendix, irritation of the vestigial remnant of the cecum and partial ileal paralysis block emptying into the cecum. → Reflexes are mediated by the myenteric plexus and by extrinsic autonomic nerves, especially by way of the prevertebral sympathetic ganglia. → IC valve dysfunction: Different symptoms are presented, which may include joint pain, sudden stabbing pain in the low back or leg, sharp/dull headaches, migraines, chronic sinus infection, allergies, dark circles under the eyes and general GI discomfort. → Large intestine: Cecum, ascending/transverse/descending colon, rectum and anus → Colon consists of functional layers with a columnar epithelium most closely opposed to the lumen, which then under-laid by the lamina propria, serosa and muscle layers. → Colonic mucosa is surrounded by continuous layers of circular muscle that can occlude the lumen. Indeed, at intervals, the circular muscle contracts to divide the colon into segments called haustra → Primary functions of the large intestine are to digest and absorb what was not more proximally, reabsorb the remaining fluid and store the waste products → Commensal bacteria engage in a life-long symbiotic relationship with their human host. These bacteria can metabolise components of the meal and make the products available to the body via fermentation. Colonic bacteria also metabolise other endogen