Suzie Rayner
Alimentary System 1.1 – The burden of GI diseases •
List the names of the organs of the alimentary tract
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Mouth and Oesophagus Stomach Liver Biliary system Pancreas Small intestine (consisting of duodenum, jejunum and ileum) Large intestine (consisting of colon, rectum and anus)
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Describe the symptoms and signs of alimentary tract disease
Symptoms: General: • Anorexia • Weight loss • Anaemia Upper GI: • Haemotemesis (vomiting blood) • Melaena (blood in the stool, black as partially digested) • Nausea and vomiting • Dysphagia (difficulty swallowing, food gets stuck on way down) • Odynophagia (pain on swallowing) • Heartburn, acid regurgitation, belching • Chest pain (heartburn, oesophageal reflux) • Epigastric pain Liver and biliary: • Right upper quadrant (RUQ) pain • Biliary colic • Jaundice (accompanied by icterus – yellowing of the sclera) • Dark urine/pale stools • Abdominal distension (Ascites) Mid GI and pancreas: • Abdominal pain • Diarrhoea • Steatorrhoea (failure to remove fat from gut content)
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Distension
Lower GI: • Abdominal pain • Bleeding – bright red stool • Constipation • Diarrhoea • Incontinence Signs: General: • Cachexia (severe weight loss) • Obesity • Lymphadenopathy (growth of nodes) • Anaemia • Jaundice • Palmar erythema • Spider navi • Stigmata of chronic liver disease Hands: • • • • • •
Koilinychia (spooned shaped nail) Leuconychia (white nail) Clubbing Dupuytreal contracture (little and ring fingers curl in on themselves) Tachycardia Tremor
Abdomen: • Organ enlargement • Mass • Tenderness • Distension Anus and rectum: • Haemorrhoids • Fistula (abnormal connection) • Fissure • Rectal masses • Proctitis (inflammation of the lining of the rectum) Abdominal distension – caused by the 5 Fs: • Fat
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Fluid Faeces Fetus Air (another word for)
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List the main diseases of the GI tract and liver
Worldwide Malnutrition Enteric infection Viral hepatitis
UK Colon Cancer
Liver disease is increasing quickly – alcohol related Chronic liver disease: • 4-6% of UK population have abnormal liver function tests (LFTs) o Hep A o Hep B o Alcohol related steato-hepatitis o Obesity related steato-hepatitis Hepatitis B: 1/3 of world’s population has been affected at some point 1 million deaths per year
Suzie Rayner
Hepatitis C: Blood-blood spread
Dyspepsia (indigestion): • Common reason for primary and secondary care • High NHS cost – drugs and endoscopies • Reduces quality of life • Risk of complication • 40% of adults have, 2% consult about it. Helicobacter pylori: • Gram negative bacteria • Spiral • Colonises gastric mucosa • Infection persists for life unless treated • 50% of worlds population is infected – linked to socioeconomic development Disease linked to H. pylori: 85% no long lasting effect 1% Gastric adenocarcinoma 14% Peptic ulceration GORD (gastro oesophageal reflux disease): • Relationship between reflux and oesophageal adenocarcinoma Liver cancer: • Most are metastases from elsewhere • Primary liver cancer (either Hepatocellular carcinoma – liver cells, or cholangio carcinoma – bile ducts) • Primary liver cancer is more common in cirrhosis Pancreatic cancer:
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95% adenocarcinoma of pancreatic duct Difficult to diagnose early
Inflammatory conditions of the intestines: • Ulcerative colitis – can result in toxic megacolon, cancer • Crohn’s disease • Coeliac disease – common in western society, due to gluten sensitivity Irritable bowel syndrome (IBS): • Idiopathic • Disorder of GI tract motility • Prevalent, especially in females • No long-term damage Biliary condition: Gall stones - Generally fat, forty, female, fertile Acute pancreatitis: • Mild-life threatening • Blocked pancreatic duct • Severe inflammation due to back up of enzymes • Ethanol and gall stones (cause?) Chronic pancreatitis: • Permanent • Alcohol is main cause • Greatly reduces quality of life Infections: Viruses Bacteria Parasite
Nora Salmonella Cholera Gardia
Anal disease: • Incontinence – more common in women due to labour (especially prolonged second stage) •
Be aware of the economic burden of GI and liver diseases
Measures of burden of disease: • Prevalence/Incidence • Morbidity (reduced quality of life, inability to work) • Mortality
Suzie Rayner • Health cost (individual, tax payer) _______________________________________________________________________
Alimentary system 1.2 – Physiological principles in alimentary tract •
Label a diagram of the alimentary system identifying the following:- mouth, oesophagus, salivary glands, stomach, pancreas, liver, gall bladder, duodenum, jejunum, ileum, colon, rectum, and anus. Mark on the diagram the position of the sphincters – gastro-oesophageal, pyloric, ileo-caecal, anal and Hepatopancreatic.
Physiological processes: • Digestion • Absorption • Excretion • Motility • Secretion GI tract is 30ft long. Input of 2l per day Output of 0.1l per day Small intestine – duodenum, jejunum, ileum Large intestine – ascending colon, transverse colon, descending colon.
Suzie Rayner
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3 pairs of salivary glands produce saliva Exocrine liver (bile) and exocrine pancreas (pancreatic juice) secrete into the duodenum via common bile duct
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Label a simple diagram of a typical gut wall section identifying: epithelial lining of gut lumen, mucosa, circular and longitudinal muscle, myenteric and submucosal plexuses and extrinsic nerves
Mucosa: • contains epithelium (cells specialised for secretion or absorption) • lamina propria (loose connective tissue) • muscularis mucosal • Invaginations may form glands with specialised cell types
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e.g. gastric gland (chief cells → pepsin, parietal cells → HCl, mucus cells → mucus) Submucosa: • connective tissue • nerve plexi • blood vessels Muscuralis: • smooth muscle • nerve plexus Serosa: • thin • peritoneum (membrane lining abdominal cavity) •
Briefly explain the terms “intrinsic” and “extrinsic” nerve supply to the gut, and how these nerves may modify secretion, absorption, motility and blood flow of the gut
[See diagram in previous learning objective] • • • • •
Interconnections between ganglia within a plexus and between submucosal and myenteric plexi Gut has high density of ganglia ‘Gut brain’ – plexi in gut Myenteric plexus – GI motility Submucosal plexus – secretion and blood flow
Blood supply to gut is due to: Coeliac artery Superior mesentery artery Inferior mesentery artery At rest, uses 30% of CO Gut acts as a ‘resevoir’ – if demand for blood elsewhere increases, the GI tract can drain to 5% CO. Hepatic portal vein – most of the blood returns to heart via this, via liver.
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State that the extrinsic nerve supply has both a parasympathetic (mainly excitatory) and a sympathetic (mainly inhibitory) component
Enteric NS – influences smooth muscle, secretory cells and endocrine cells. Parasympathetic (mainly excitatory) – Vagus and Pelvic nerves Sympathetic (mainly inhibitory)
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Explain that mechano- and chemoreceptors in the gut wall may invoke both local reflexes involving the intrinsic nerve system and “long” reflexes involving the brain via afferent nerve fibres in the vagus and splanchnic nerves Chemoreceptors and mechanoreceptors in the gut wall feedback to plexi in the gut wall (local afferent) and feedback to CNS (via splanchnic and vagal afferent) Efferent output influence: • Muscularis externa • Muscularis mucosae • Endocrine cells • Secretory cells • Blood vessels
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Describe how the activity of the gut muscles mixes contents with the digestive secretions and also aids efficient absorption of nutrients
Gut has 2 layers – circular and longitudinal Stomach has extra 3rd layer – oblique – powerful contractions occur here, grinds food before entering the small intestine Gastric emptying solid meal – approx 3 hours Liquid meal – approx 1 hour Small intestine – approx 12 hours Colon – approx 12-48 hours Mixing movements: • Circular smooth muscle contracts • Contents mixed with digestive secretions • Local effect – contents, wall stretch • Aids absorption – fresh material to mucosa • Does not require CNS input Peristalsis: • Organised movement over 10cm segment of gut • Relaxation precedes region contraction • Requires CNS input •
Describe how the structure of the mucosal lining of the gut leads to a large surface area for absorption
3 layers of folding: • Mucosal folds • Villus structure • Brush border of luminal membrane of epithelial cells • •
State that the maximum rates of absorption of fat, protein and carbohydrate are about 10x greater than the normal daily rates State that some 7 litres of fluid are secreted into the gut lumen during a day • Explain the importance of the reabsorbtion of this secreted fluid.
Large proportion of extracellular fluid in GI secretions, therefore important to reabsorb.
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State that nearly all of the nutrients and most of the fluid secreted by the gut is reabsorbed in the small intestine Total daily input → GI: 9.5l (food and secretions) Fluid absorbed by osmosis None absorbed by stomach Approx 8l in small intestine Approx 1.4l in large intestine 100-150ml lost in faeces •
Describe how gut function is regulated by a combination of neural (both central and local), humoral and local paracrine activity. Illustrate this with a suitable example
Control of GI tract – regulates absorption, secretion, motility and blood flow. Negative feedback response [Stimulus – response – effect – feedback] 3 phases: Cephalic (neural reflex): approach of food (sight, smell), food in mouth (taste) Gastric (paracrine and hormonal): stomach Intestinal (products stimulate or inhibit acid): small intestine Neural: • Intrinsic • Extrinsic Humoral: • Secreted by gut – secretin • And other glands – e.g. aldosterone, increases Na uptake in colon • Local hormones – paracrine control – histamine in stomach Parietal cell Stimulated by: Acetylcholine (Ach) – Vagus Gastrin (G receptor) – G cell Histamine (H receptor) – ECL Amplification occurs due to Vagus stimulating G and H, and Gastrin stimulating H. Also various inhibitory mechanisms that modify/oppose stimulation.
Suzie Rayner Initiation: • Vague reflex starts acid before food enters stomach • Direct and Indirect stimulation Maintenance: • Stretch of stomach wall by contents causes further gastrin release Termination: • Cessation of vagal stimulants (food) • Emptying stomach reduces wall stretch – reflexes decrease • Other inhibitory mechanisms from small intestine Cell Wall Junctions:
Epithelial junction transport: • Electro-chemical gradient • Tight – big gradient – stomach (also maintain proteins in correct lamina region) • Leaky – small gradient – small intestine • Colon is between tight and leaky Membrane transport: • Diffusion • Facilitated transport • Active transport Involves 2 types of transport protein: • Channel proteins – forming aqueous pores allowing specific solutes through • Carrier proteins – bind to solute and undergo a conformational change to transport it across the membrane • Channel are FASTER than Carrier Ion channel transport: • Electrochemical gradient
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Anion or Cation – not both Ion specific Open or closed E.g. basolateral K+, Luminal Cl-
Various types of ion channel: • Voltage gated • Ligand gates (extracellular, intracellular ligand) • Mechanically gated Carrier mediated transport: • Uniport – 1 molecule passes one direction • Symport – 2 molecules pass one direction (co transportation) • Antiport – 2 molecules pass in opposite directions (maintain cell charge as exchange like for like charge) Ion exchanger transport: • Electrochemical gradient • Anion or cation • Ion specific • Electroneutral • e.g. Na+/H+, Cl-/HClPrimary active ion transport: • Against electrochemical gradient • Therefore, requires ATP • Ion specific • May be electrogenic • May establish electrochemical gradient • e.g. Na+/K+, H+/K+ (proton pump) Na+: • • • •
Provides much of power driving ion movement due to Na gradient in epithelial cells Maintained by ATP driven sodium pump Na+/K+ pumps – use 30% ATP in normal cells, 70% in neurons Na+ gradient powers a number of other transporters (secondary active transport)
Endogenous messengers (cAMP, Cl- channel) and exogenous drugs (proton pump inhibitors) may modify ion transport activity.
Alimentary system 2.1 – Oesophagus and stomach
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List the main functions of the oesophagus
Conduit for food, drink and swallowed secretions from pharynx to stomach •
Define the anatomical levels and relations of the oesophagus
• • • • • • •
Transition from skeletal to smooth muscle Oesophagus passes through the diaphragm at T10. Anteriorly: trachea, fibous pericardium Posteriorly: Prevertebral muscles, vertebra bodies, descending aorta Thoracic duct passes posterior to oesophagus between T7 and T4 Recurrent laryngeal nerves in groove between trachea and oesophagus. Passes through inferior neck and superior and posterior mediastinum
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Summarise the organisation of muscle types and function within the oesophagus
The muscle coats of the oesophagus are continuous with the laryngopharynx. Transition from skeletal to smooth muscle •
Define the structural basis for the gastro-oesophageal sphincter
Lowest part of inferior constrictor (cricopharyngeus) is upper oesophageal sphincter Gastro-oesophageal junction: • Prevention of reflux is mainly due to the diaphragm muscle (rather than oesophageal smooth muscle) • Transition from stratified squamous to gastric glandular epithelium normally occurs just below diaphragm (zigzag line) • If sphincter weakens, regurgitation of gastric secretion may occur.
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Define the epithelial type that lines the oesophagus and explain how this is adapted to its function
Suzie Rayner Non-keritinising stratified squamous epithelium • ‘Wear and tear’ function • Subjected to extremes of temperature and texture Lubrication by saliva and local mucus-secreting glands in oesophageal wall • • • • • •
List the main functions of the stomach Site of digestion of food in acid environment Principally digested by pepsin Little absorptive function Contents mixed (with secretions) by complex kneading movement of smooth muscle Retain contents for variable time (mins-hours)
Structure: • Oesophagus enters stomach at cardia when there is less curvature between fundus and body • Antrum tapers to pyloric sphincter • Suspended in mesenteries by lesser and greater omenta and gastrosplenic ligament • Gastro-oesophageal sphincter depends on diaphragm • Foregut derivative receiving blood from all 3 branches of coeliac axis • Parasympathetic nerves from vagus • Sympathetic from T6-T8 via coeliac plexus
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Demarcate the functionally distinct regions of the gastric mucosa
In gastric body and fundus: • Mucus-secreting pit • Proliferative neck region • Glands with chief and parietal cells Gastric mucosa: • Simple epithelium throughout (single cell layer) • Blind-ending simple glands throughout (‘crypts’ in intestine) • Glands secrete into pits in stomach • Covered in conical pits leading to gastric glands • Entire surface covered in rugae – fixed ridge-like longitudinal folds • Villi in small intestine only (duodenum, jejunum and ileum) • •
Sketch and label a typical acid secreting and enzyme secreting gastric glands, showing the pit, neck and gland, the location of the epithelial stem cells and of surface mucous cells, parietal cells and chief cells Summarize the functions of the previous cell types
Gastric glands: • Tubular glands lying entirely within the mucosa • Arise from bottom of gastric pits • Glands of fundus: secrete HCl and enzymes [Mucus and bicarbonate ions protects epithelium from HCl and pepsin – neutralises acid before reaching cell wall]
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Using simple diagrams, explain the mechanism of secretion of pepsinogen by the chief cells Chief cell: • Secretes Pepsinogen (inactive proenzyme, cleaved by HCl) • Typical protein secreting epithelial cell
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Abundant RER Golgi packaging and modification for export Masses of apical secretion granules
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Using simple diagrams, explain the mechanism of secretion of HCl by the oxyntic cells Parietal cell (Oxyntic): • HCl secreted • Uses apical proton pump ATPase in tubulovesicle membrane • When activated, bring pump membrane into apical surface. Resting: • Many mitochondria • Cytoplasmic tubulovesicles • Internal canaliculi (small passageways) Secreting: • Elaborate bell-shaped canaliculus open to gland lumen • Tubulovesicles absent •
Summarize the control of gastric secretion and outline the basis for the use of H2 inhibitors and proton pump inhibitors in pharmacological control of gastric acid secretion
Control of gastric acid secretion [mentioned in lecture 1:2] • Stimulation by taste, smell, thought, food in stomach • Neural - vagal parasympathetic • Endocrine – Gastrin • Final common pathway is intramucosal histamine release from ECL cells • Omeprazole – Proton pump inhibitor • Ranitidine – H2 blocker, inhibits histamine Localisation of H+, K+ and ATPase • Can be localised by immunohistochemistry or enzyme histochemistry (chemical composition of cells and tissues) • Associated with tubulovesicles and canaliculi • Parietal cells have strong activity of carbonic anhydrase II (generates H+ by ionisation of H2CO3) – parietal cells stain by Hansson method due to carbonic anhydrase present. Chromaffin cells – release histamine • Numerous in lamina propria connective tissue between gastric glands • Respond to ACh (vagus parasympathetic), Gastrin and local inflammation • Releases histamine which stimulates parietal cell – H2 receptors G cells – release gastrin • numerous endocrine G cells in mucosa of pyloric antrum and duodenum
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Nerves and local peptides stimulate release (Big- G34, Little – G17) Diffuses to stimulate histamine release
3 phases of gastric secretion [briefly mentioned in previous lecture]: Cephalic: • Neural stimulation (thoughts) • ACh stimulates parietal, chief, mucus, G cells. • Gastrin also stimulates parietal → more HCl • ECL cell stimulates by ACh and gastrin → histamine released • Histamine stimulates parietal H2 receptor. Gastric: • Stimulated by distension, peptide fragments, caffeine, ethanol. • Short reflexes(stimulate parietal and chief cell) • Long reflexes (via vagus) • Neural and direct response • Gastrin stimulates parietal and chromaffin cell (HCl and histamine release) Intestinal: • Inhibitory (and excitatory but less so) • Enterogastrone (from duodenum) – inhibits gastrin • Fall in peptide conc. decreases stimulus • Decrease in pH inhibits gastrin secretion • [Excitatory – peptides in duodenum release gastrin] _______________________________________________________________________ _
Alimentary system 2.2 – Gastro-oesophageal reflux disease (GORD) Objectives Oesophageal symptoms • Dysphagia - approach to patients Gastro-oesophageal reflux disease • pathophysiology – lower oesophageal function and hiatus hernia • management – lifestyle change, antacids, acid suppression and surgery Oesophageal motility • normal oesophageal motility • achalasia – paradigm of control of oesophageal motility • other motility disorders Oesophageal neoplasms • benign • malignant – relationship with reflux disease, principles of palliation
Suzie Rayner Glossary: Acid suppression
Medication aimed at reducing amount of gastric acid production, and hence oesophageal exposure to acid; the two main classes are H2-receptor antagonists (directed at the Histamine-2 receptors on gastric parietal cells) and proton pump inhibitors (blocking the H+/K+ ATPase pump on gastric parietal cells).
Ambulatory pH monitoring Measurement of amount of gastric acid the oesophagus is exposed to over a prolonged period of recording (usually 24 hours) Angle of His
The acute angulation of the stomach with respect to the oesophagus – contributes to the anti-reflux mechanism
Barrett’s oesophagus
Localised areas of columnar epithelium occurring in the distal oesophagus in response to chronic reflux – rarely may be a pre-malignant lesionin the development of oesophageal adenocarcinoma
Fundoplication
Surgical correction of hiatus hernia or incompetent lower oesophageal sphincter
Hiatus Hernia
Upward displacement of stomach through diaphragmatic hernia into thorax
Lower Oesophageal
Condensation of oesophageal smooth muscle in Sphincter distal oesophagus, comprising the major contribution to the anti-reflux mechanism
GORD – Symptoms or mucosal damage produced by abnormal reflux of gastric contents into the oesophagus. Gastro-oesophageal junction [See diagram in previous lecture]: • Prevents reflux of gastric contents • Opens for swallowing • Vents gas selectively (belching) • Opens for vomiting Prevents reflux by: • Oesophageal sphincter • Crura/diaphragm • Angle of His (flap valve) [If mechanisms fail, GORD occurs] Epidemiology: Atleast weekly heartburn/acid regurgitation:
Suzie Rayner 5-10% of Western world 5% of asia Chronic symptoms (>2x weekly): 6% heartburn 3% acid regurgitation Pathophysiology of reflux (reasons it occurs): Hypotensive lower oesophageal sphincter(transient relaxations) – sphincter is not tight enough. • 4cm of increased smooth muscle tone (not an anatomical sphincter) • Minority of GORD patients have low fasting pressure • Many factors decrease lower oesophageal sphincter (gastric distention, fat, chocolate, caffeine, alcohol, smoking, drugs) Anatomic disruption of the gastro-oesophageal junction (hiatus hernia) [see diagram] • 75% of GORD patients have hiatus hernia • Increases with age and obesity • Low LES and HH is more than additive (much increased risk of GORD) • Occurs when flap valve disappears, so top part of stomach slides through diaphragm
decreased neutralization
Delayed oesophageal acid clearance • Dysmotility • Hiatus hernia • Severe oesophagitis causing fibrosis – decreased peristalsis and acid removal • Cigarette smoking – hyposalivation →
Symptoms: • Acid regurgitation • Retrosternal burning ‘Heart burn’ • Atypical chest pain/waterbrash • Dysphasia (difficulty in swallowing) • Chronic cough • Globus (feeling of lump in throat)
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Asthma
Pathology: • Barrett’s oesophagus • Stricture • Oesophagitis • Adenocarcinoma (reflux increases risk) Diagnosis: • Typical history – heartburn, regurgitation • Atypical history – dysphagia, odynophagia, waterbrash, globus, asthma, chest pain, cough, hoarse voice Investigate further if: • No response to anti-acids • Unusual history • Severe symptoms to look for complications • New symptom at age when concerned (cancer) • Alarm symptoms Investigations: • Endoscopy • pH manometry (wear through day) NERD (non-erosive reflux disease) • 70% of patients with symptoms do not have erosive oesophagitis [Symptoms and normal 24 hour pH – visceral hyperalgesia/Bernstein text +ve] [Abnormal 24 hour pH but normal mucosa – pepsin/tight junctions/H+ channels • ‘Functional heartburn’ – symptoms not due to acid reflux, Bernstein text –ve.
GORD treatment:
Suzie Rayner
Lifestyle modification – bed elevation, diet, meal times, weight loss, smoking, clothing Medical therapy: • Antacids – bicarbonates (rennies)/milk, alginates (gaviscon) • H2 receptor antagonists – ranitidine, cimetidine • Proton pump inhibitor – omeprazole, esomeprazole Surgical therapy – Nissen’s fundoplication If poor response to treatment: • Review compliance • Increase acid suppression • Change proton pump inhibitor • Add H2 antagonist at bedtime • Surgery Surgery complications: • More risky • Side effects of dysphagia, inability to vomit, perforation • Reserved for difficult patients New discoveries: Clostridium difficile and PPIs - PPI therapy is risk factor for Clostridium difficileassociated diarrhoea Asthma and reflux- gastro-oesophageal reflux and respiratory disease show a relationship – 30-90% incidence of reflux symptoms in asthmatics Proposed links:
Suzie Rayner
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Alimentary system 3.1 – Duodenum, Jejunum and Ileum • List the main functions of the small intestine. To absorb nutrients, salt and water.
• Distinguish between the duodenum, jejunum and ileum There is no sudden transition between the duodenum, jejunum and ileum. All have same basic histology, but some general differences. Length
Duodenum 25cm
Jejunum 2.5m
Ileum 3.75m
Duodenum: Identified by presence of Brunner’s glands • Submucosal coiled tubular mucous glands, secreting alkaline fluid • Open into base of crypts • Alkaline secretions neutralise acidic chime from stomach (protects proximal small intestine) and helps optimise pH for action of pancreatic digestive enzymes. Jejunum:
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Characterised by presence of numerous large folds in submucosa – plicae circulares The plicae are also present in rest of small intestine, but are taller, thinner and more frequent in jejunum ‘Frilly’ interior
Ileum: • Has a lot of Peyer’s patches – large clusters of lymph nodules in submucosa. • Prime immune system against intestinal bacteria (Other defence – bactericidal paneth cells, rapid cell turnover) • Well position to prevent bacteria from colon migrating up small intestine Ileum and colon: • Ileum is separated from colon by ileocaecal sphincter • Relaxation and contraction control the passage of material into the colon and prevents backflow of bacteria into the ileum Adaptation of small intestine for absorption: • Movement o External wall-longitudinal o Circular muscle • Increased SA o Internal mucosa arranged in circular folds o Mucosa covered in villi o Invaginations – crypts of Lieberkuhn Villi: • Motile • Rich blood supply and lymph drainage for absorption of digested nutrients • Good innervation from submucosal plexus • Simple epithelium dominated by enterocytes (columnar absorptive cells) •
Draw a labelled sketch of the mucosa of the small intestine to explain the nature of villi and crypts.
Cell Type Enterocyte
Goblet cells Enteroendocrine cells Paneth cells Stem cells
Action • Absorption • Covered by microvilli • Most abundant • Frequent renewal • Mucous secreting • Hormone secreting • Antibacterial • Protect stem cells • Migrate up villus ‘escalator’
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Pluripotent
Mucosa - Lined with simple columnar epithelium consisting of • Primarily enterocytes (absorptive cells) • Scattered goblet cells • Enteroendocrine cells (endocrine in GI tract) Crypts of Lieberkuhn – epithelium includes • Paneth cells • Stem cells Paneth cells: • Found only in base of crypts • Engulf some bacteria and protozoa • May have role in regulating intestinal flora • Contain large acidophilic granules. Granules contain: • Lysozyme (antibacterial enzyme) • Glycoproteins and zinc
Enterocytes: • Most abundant cells in small intestine • Tall columnar cells • Microvilli and basal nucleus • Specialised for absorption and transport of substances • Short lifespan (1-6 days) Microvilli: • Make up brush border • Approx 0.5-1.5μm high • Several thousand microvilli per cell
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Covered with glycocalyx o Rich carbohydrate layer on apical membrane o Protects from digestional lumen, yet allows absorption o Traps layer of water and mucous (unstirred layer) which regulates rate of absorption from intestinal lumen
Surface area is increased by folds, villi and microvilli. Goblet cells: • 2nd most abundant epithelial cell type • Increase in abundance along the entire length of the bowel • Mucous containing granules, accumulate at apical end – gives goblet shape • Mucous o Mucous is large glycoprotein that facilitates movement of material through the bowel
Suzie Rayner
Enteroendocrine cells: • Columnar epithelial cells, scattered amongst absorptive cells • In the intestine, most often found in the lower part of crypts • Hormone secreting – e.g. influence gut motility • •
Describe the source and migration route of newly formed enterocytes and explain how enterocytes are adapted for absorption. Compare the turnover time of intestinal epithelium with epithelia from other sites. Describe the structure/function relationship of the digestive epithelium.
Continuous processes of cell proliferation, differentiation and death. Enterocytes and goblet cells of small intestine have life span approx 36 hours. Continually replaced by dividing stem cells. Stem cells: • Undifferentiated cells which remain capable of cell division to replace cells which die • Epithelial stem cells are essential in the GI tract to replenish the surface epithelium • Continually divide by mitosis • Act as ‘escalator’ of epithelial migration • Divide in crypts, migrate up to tip of villus, replacing older cells that die • Cells become senescent at villus tips → sloughed into the lumen of the intestine and digested and reabsorbed Rapid turnover due to: • Enterocytes as first line of defence against GI pathogens and may be directly affected by toxic substances in the diet • If ‘escalator-like’ transport fails, the production of new cells is impaired → severe intestinal dysfunction occurs. Cholera • Cholera enterotoxin – results in prolonged opening of chloride channels in small intestine, allowing uncontrolled secretion of water • Leads to rapid dehydration and death • Treatment is rehydration, cholera bacteria clear, epithelium is replaced.
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Describe the structure/function relationship of the circular muscles.
Motility – 3 principles: • Mix indigested food with digestive secretions and enzymes • Facilitate contact between contents of intestine and intestinal mucosa • Propel intestinal contents along alimentary tract Segmentation: • Mixes the contents of lumen • Occurs by stationary contraction of circular muscles at intervals • More frequent contractions in duodenum compared to ileum – allows pancreatic enzymes and bile to mix with chyme • Net effect of movement of chyme towards colon, although chyme does move in both directions. Peristalsis: • Sequential contraction of adjacent rings of smooth muscle • Propels chyme towards colon • Most waves of peristalsis travel about 10cm Migrating motor complex • Occurs in fasting more than in fed state (but does occur in both) • Cycles of smooth muscle contractions • Stomach → small intestine → colon (on reaching terminal ileum, next contraction starts in duodenum) • Prevents migration of colonic bacteria into ileum • May ‘clean’ intestine of residual food • Explain the principles, and summarise the mechanism, of digestion and absorption of carbohydrates, proteins and lipids in the small intestine. Digestion in duodenum: • Digestive enzymes and bile enter the duodenum from the pancreatic duct and bile duct • Digestion in small intestine occurs in alkali environment • Duodenal epithelium also produced digestive enzymes • Digestion occurs in lumen and in contact with the membrane Carbohydrate digestion: • Begins in mouth by salivary α-amylase • This is destroyed in the stomach due to acidic pH • Most carbohydrate digestion occurs in small intestine. Duodenum secretes pancreatic α-amylase in response to a meal • Continues digestion of starch and glycogen in small intestine.
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Needs Cl- for optimum activity and neural/slightly alkali pH – supplied by Brunner’s glands Carbohydrates are broken down from complex carbohydrates → disaccharides/oligosaccharides → monosaccharides which can be absorbed by enterocytes. Absorption of carbohydrates Monosaccharide Glucose and Galactose Fructose
Absorption mechanism Secondary active transport – carrier protein and electrochemical gradient Facilitated diffusion
Carrier protein SGLT-1 on apical membrane GLUT-5 on apical membrane
GLUT-2 facilitates exit at basolateral membrane. Protein digestion: • Begins in stomach by pepsin • Pepsin is inactivated in alkaline duodenum • Pancreatic proteases are secreted as precursors. • Trypsin is activated by enterokinase (enzyme located on duodenal brush border) • Trypsin activates other proteases. Absorption of protein: • Amino acids absorbed by facilitated diffusion and secondary active transport • Brush border peptidases break down larger peptides prior to absorption • Di and tri peptides are absorbed using carrier proteins distinct from single AA • Cytoplasmic peptidases break down most of di and tri peptides before they cross basolateral membrane. Lipid digestion: • Poorly soluble in water – complicated to digest Four stage process: • Secretion of bile and lipases • Emulsification • Enzymatic hydrolysis of ester linkages • Solubilization of lipolytic products in bile salt micelles _______________________________________________________________________ _
Alimentary System 3.2 – Malabsorption •
To recognise the clinical presentation of malabsorption
Diarrhoea:
Suzie Rayner
Symptoms Clinical Change in consistency of stools Increased volume of stool Urgency to defecate/uncontrollable (Increased frequency) Increased frequency Normal frequency of bowels: 3x per day to 3x per week Normal volume: <200ml/day Investigate diarrhoea: When last longer than 2 weeks (as infectious diarrhoea rarely lasts longer than 2 weeks) Chronic diarrhoea has many causes – osmotic, secretory, inflammatory. Steatorrhoea: • Pale poorly formed stools • Offensive smell • Difficult to flush • Oil rings • Faecal leakage Normal faecal fat content <6g/day Nutritional assessment: • Questions – lost weight recently, normal weight/height • Height and weight MUST (Malnutrition universal screening tool) Step 1 – BMI Score Step 2 – Weight loss score Step 3 – Acute disease effect score – no nutritional intake for >5 days Step 4 - Overall risk Step 5 – Treatment
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Examination: • Muscle wasting • Loss of fat • Oedema/ascites • Low albumin • (anaemia, skin lesions, hair loss, poor wound healing, purpura etc) Nutrition: Fats Amino acids and Protein Carbohydrates Electrolytes and water Minerals Trace elements Vitamins [FACE MTV] Growth failure/Weight loss Tests for malabsorption:
Suzie Rayner Fats – steatorrhoea (clinical +/- faecal fat) Protein and nitrogen – urinary excretion, albumin Minerals – iron, calcium, magnesium, zinc Vitamins – B12 (cobalamin), D (calciferol), folate, vitamin K, carotene Functional absorption tests: Intestinal intubation: Lundh meal Tubeless tests: Xylose and other sugar tests Pancreolauryl test Schilling test Many other (little clinical use) Diagnostic focus is on defining pathology: Endoscopy to do biopsy and histology Radiology to see structural changes Enteroscopy: • Since 2001 • Disposable capsule • 2 frames per second • 8 hours battery life • Recording system warn externally
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Rare inherited disorders: • Cystinuria • Fructose malabsorption • Glucose-galactose malabsorption [Disorders associated with non-functional transporters can present in childhood] MANY more •
To understand the disease mechanisms leading to malabsorption
Common malabsorptions of specific nutrients Nutrient Condition Lactose Lactase non-persistence Vitamin B12 Pernicious anaemia Bile salts Bile salt diarrhoea
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Lactose: • Hypolactasia in the small intestinal brush border membrane is usual adult human phenotype (non-persistence of neonatal lactase) • Persistence of lactase activity occurs in most northern Europeans • Malabsorption of lactose in small intestine gives symptoms from breakdown in the colon. • Diagnose from history, lactose-H2 breath test Short bowel syndrome: • Usually after surgery for Chron’s disease, infarction or trauma • Less than 200cm of small intestine leads to o Malabsorption o Malnutrition o Electrolyte imbalance o Progressive weight loss Small bowel disease requires nutritional support for intestinal failure. •
To learn about the clinical importance, presentation, complications and treatment of coeliac disease
Coeliac disease: Inflammatory disease of the upper small intestine, resulting from gluten ingestion in genetically susceptible individuals. Presentation: • Typical • Atypical • Asymptomatic (silent) Adult symptoms: Frequent (>50%) Malaise/fatigue Steatorrhoea Diarrhoea Weight loss
Common (>25%) Anorexia Abdo pain Oral ulcers Distension/bloating Childhood history
Childhood symptoms: • Diarrhoea, steatorrhoea • Abdo distension • Weight loss • Failure to gain weight • Lassitude (weakness, weariness) • Abdo pain • Anorexia
Occasional (<25%) Nausea Muscle/bond pain Bruising/rashes Oedema Constipation
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Vomiting Irritability Resp. infections
[CHANGING PRESENTATION – as less reliant on wheat based diet, many nonspecific symptoms] Investigations: Anaemia: >50% (macrocytic, normocytic, microcytic) • Iron deficiency – 50% • Folate deficiency – 90% • B12 deficiency – 30% Low protein: Hypoalbuminaemia – 40% Calcium and mineral disorders: • Low calcium • Increased alk.phos. • Decreased 25 hydroxycholecalciferol • Increased parathyroid hormone Other occasional occurances: • Increrased prothrombin time • Decreased zinc • Decreased magnesium • Other vitamin deficiencies • Abnormal transaminases Endomysial antibodies in coeliac disease • Similar to reticulin/jejunal antibodies • Detected by indirect immunofluorescence o Primate oesophagus o Gastric/small bowel muscle o Umbilical cord • IgA class • High specificity (>95%) and sensitivity in diagnosis • Useful in monitoring response to treatment Autoantibodies Antiglandin antibodies – less specific than endomysial antibodies Tissue transglutaminase: • Autoantigen recognised by endomysial antibodies • tTG cross-links glutamine residues including those in gliadin • Produce neo-antigens • Measured by ELISA
Suzie Rayner Coeliac iceberg:
Dermititis herpetiformis: Vesicular rash • Intense pruritus (itching) • Blisters rarely present • Especially at arms and shoulders Skin biopsy • Granular IgA deposits Associated villous atrophy and gluten-sensitivity Screening populations for coeliac disease: Groups with prevalence between 1-5% (in general pop. it is approximately 1%) • Type 1 diabetes • Thyroid disease • Anaemic blood donors • Irritable Bowel syndrome • Osteoporosis Gluten sensitivity enteropathy (pathology of gluten sensitivity in the intestines) Gluten is • Fractions of cereals that binds • Specifically polypeptides rich in Q and P
•
e.g. Residues 57-89 of α2-gliadin has many P and Q
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Stable in gastric, pancreatic and intestinal proteases Reacts with tTG (tissue transgluaminase) This stimulates HLA-restricted intestinal T cell clones from coeliacs
[NOTE: HLA = MHC (major histocompatibility complex)] Sensitivity: • Immunological response – tTG and neo-antigen formation, activated HLArestricted T-lymphocytes • Genetic predisposition to immune response – shown by twin and family studies (10-12% risk in 1st degree relatives, 70% risk in monozygotic twins) Different classes of HLA have different functions: Class I antigens (A,B,C) – present peptides from inside the cell Class II antigens (DR, DP, DQ) – present phagocytosed antigens from outside the cell HLA associated with coeliac disease: HLA-A1, HLA-B8, HLA–DR3 HLA-DQ2 – 95% northern European coeliac patients, 20% non-coeliac control In HLA matched siblings, concordance for coeliac disease is approx 30%, therefore other genes must be involved. Enteropathy: • Inflammatory damage • Cell death (apoptosis) • Histological changes – enterocyte apoptosis, stimulated regeneration • Functional changes leading to malabsorption of nutrients Principles of treatment: • Gluten-free diet • Maintain adequate nutrition with o Gluten-free products on prescription o Nutritional supplements o Prevent complications Resistance disease occurs due to: • Failure to understand dietary principles – education by dieticians about gluten free diet/products • Difficulty adhering to diet – eating out, peer pressure, family meals • Hidden sources of gluten • Consider alternative/additional diagnoses Complications associated with coeliac disease: • Nutrition malabsorption, therefore impaired nutritional status • Small bowel malignancy – lymphoma, adenocarcinoma
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Osteoporosis/osteopenia (low bone mineral density)
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Alimentary system 4.1 – Pancreas: Structure-function relationships •
Distinguish between the exocrine and endocrine parts of the pancreas in structural and functional terms Endocrine: secretion into blood stream to have effect on distant tissue/organ, ductless glands Exocrine: secretion into gland to have direct local effect Endocrine hormones: Insulin: Decreases blood glucose, therefore anabolic hormone, promotes transport into cells and storage as glycogen, promotes protein synthesis and lipogenesis. Glucagon: Increases blood glucose, therefore increases gluconeogenesis and glycogenolysis Somatostatin: ‘Endocrine cyanide’ – inhibits insulin and glucagon Endocrine: • 2% of gland • Islets of Langerhans • Secretes hormones into blood (Insulin, glucagon, somatostatin) • Regulation of blood glucose, metabolism and growth effects Exocrine: • 98% of gland • Secretes pancreatic juice into duodenum via pancreatic duct/common bile duct • Digestive function Pancreatic cell differentiation: Exocrine Ducts Acini – grape-like clusters of secretory units Acinar cells secrete pro-enzymes into ducts
Endocrine Derived from the branching duct system Lose contact with ducts – become islets Differentiate into α and β-cells secreting into blood Tail has more abundant islet tissue than head
Pancreatic disease may involve both exocrine and endocrine effects.
Suzie Rayner Islets of langerhans: [REVIEW OF ENDO] α cells Glucagon 15-20%
β cells Insulin 60-70%
δ cells Somatostatin 5-10%
Islets are highly vascular, so that endocrine cells have close access to a site for secretion. •
Outline the embryonic development of the pancreas
Development of pancreas: • • • • •
•
A foregut derivative arising at the foregutmidgut junction Dorsal and ventral buds Ventral bud is part of hepatobiliary bud Duodenum rotates – forming C shape Ventral bud swings round, lies adjacent to dorsal bud – both buds fuse Ventral bud duct → main pancreatic duct
• Review the anatomical regions and main anatomical relations of the pancreas Subdivided into head, neck, body, tail and uncinate. Islet tissue is most abundant in tail.
Pancreatic juices mainly reach duodenum via main pancreatic (and accessory) ducts. Anatomy:
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Lies mainly on posterior abdominal wall Extends from C-shaped duodenum to hilum of spleen Main posterior relations: IVC, abdominal aorta, L kidney. Close relation, with supply from, celiac and superior mesenteric arteries
Pancreatic juice:
Two components of pancreatic juice: Acinar cells • Secrete low volume, viscous, enzyme-rich. • Large with apical secretion granules Duct and centroacinar cells secrete high volume, watery, HCO3-rich •
Sketch the duct system of the pancreas
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Define a pancreatic acinus Describe the subcellular organisation of synthesis and secretion by the pancreatic acinar cells List the most important components of the pancreatic (exocrine) secretions and define their roles in digestion Explain the mechanism for bicarbonate secretion in terms of ion exchange pumpsb and membrane ion channels and the dependence on active transport
Bicarbonate secretion: • Duct and centroacinar cells • Juice = rich in bicarbonate – approx. 120mmol/l (plasma is 25mmol/l) • Neutralises acid chime from the stomach o Preventing damage to duodenal mucosa o Raises pH to optimum range for pancreatic enzymes • Washes low volume enzyme secretion out of pancreas into duodenum As duodenal pH drops, rate of production of bicarbonate increases: >5 = significant linear increase >3 not much more increase (plateaus) Bicarbonate secretion stops when pH is still acidic due to: • Bile containing bicarbonate • Brunners glands secreting alkaline fluid Mechanism for bicarbonate secretion: Pancreatic HCO3 secretion: • Catalysed by carbonic anhydrase • Separation of H+ and HCO3• Na+ moves down gradient via paracellular • H2O follows Na+ • Cl/HCO3 exchange at lumen • Na/H exchange at basolateral membrane into bloodstream The exchanges are driven by electrochemical gradients. • Na gradient into cell from blood, maintained by Na/K exchange pump • Uses ATP • K returns to blood via K channel • Cl returns to lumen via Cl channel Same reaction in gastric parietal cells (acid) and pancreatic duct cells (alkaline) Stomach: H+ goes into gastric juice, HCO3- into blood (gastric venous blood is alkaline) Pancreas: HCO3- into juice, H+ into blood (pancreatic venous blood is acidic) •
Understand that acinar cells synthesise enzymes for the digestion of carbohydrate, lipids and proteins and store these in an inactive form in zymogen
Suzie Rayner granules, and explain how these enzymes are activated when they enter the duodenum Acinar cell enzyme secretion: • Enzymes for digestion of fats, protein, carbohydrates are synthesised and stored in zymogen granules (lipase, protease, amylase) • Zymogens = pro-enzymes • Proteases are released as inactive pro-enzymes – protects acini and ducts from auto-digestion • Pancreas contains a trypsin inhibitor to prevent trypsin activation • Enzymes only become activated in duodenum • Blockage of pancreatic duct (e.g. due to mucus from CF) may overload protection, resulting in auto-digestion – Acute pancreatitis • Enterokinase secreted from the duodenum, converts trypsinogen → trypsin • Trypsin then converts all the other proteolytic and some lipolytic enzymes [Lipase is secreted as active form but requires colipase which is secreted as a precursor and bile salts to activate] Altered pancreatic enzyme function: • Pancreatic secretions adapt to diet • Pancreatic enzymes (and bile) are essential for normal digestion of a meal. Lack of them can lead to malnutrition. • Anti-obesity drug Orlistat inhibits pancreatic lipases – steatorrhoea (when lipase secretion is significantly reduced) •
Explain how nervous stimulation and the hormones secretin and CCK regulate the release of pancreatic juice.
Control of secretion: Vagus nerve – cholinergic, communicates from gut → brain Cephalic phase: • Reflex response to sight/smell/taste • Enzyme rich component only. Low volume – mobilises enzymes Gastric phase: • Stimulation of pancreatic secretion originating from food arriving in the stomach • Same mechanisms involved as for cephalic phase Intestinal phase (70-80% pancreatic secretion) • Hormonally mediated when gastric chime enters duodenum • Both components of pancreatic juice stimulated The two components of pancreatic juice are separately controlled: Bicarbonate: controlled by hormone release - secretin
Suzie Rayner Enzyme secretion: controlled by vagal reflex and hormone cholecystokinin(CCK) (also stimulates bile secretion)
Switching of CCK: • Cephalic phase when meal eaten • Absorption of fats and peptides remove stimulus for CCK release from mucosa Stimulus interaction Affect of addition – greatly increasing. Vagus nerve has similar affect to CCK Secretin has no effect on enzyme secretion.
In summary, during a meal:
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Food mixed, digested in stomach, pH 2 Chyme squirted into duodenum H+ ions in duodenum stimulate secretin, stimulating release of pancreatic juice, bile and brunner’s gland secretions to increase pH. Peptides and fat in duodenum cause increase in CCK, vagal nerve, stimulating pancreatic enzyme release → continues until stomach empty CCK potentiates effects of secretin on aqueous component.
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Alimentary 4.2 – Pancreatitis General anatomy of area containing pancreas:
•
Define acute and chronic pancreatitis Acute pancreatitis: Acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems. Chronic pancreatitis: Longstanding inflammation of the pancreas that alters its normal structure and functions. •
List four causes of acute pancreatitis
Most common causes: alcohol, cholelithiasis (gallstones) Other causes: metabolic, infection, medication, vasculitis • List three causes of chronic pancreatitis Alcoholism, microlithisasis, idiopathic. •
List the symptoms and signs of acute pancreatitis
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Patient presents with: • Very variable • Abdo pain radiating to back • Vomiting • Organ failure • Jaundice, cholangitis (bacterial infection superimposed on blockage of biliary tree) Diagnosis of acute pancreatitis: • Clinically (pain and vomiting) • Elevated pancreatic enzymes (lipase lasts longer and is more specific than amylase) • Chest X-Ray (to exclude perforated ulcer) • Ultra sound (for gall-stones) • CT scan (in doubtful cases, excludes other pathology) •
List blood tests and imaging modalities which are useful for patients with pancreatitis
Determining cause of pancreatitis: History: • Previous gall stones • Alcohol intake • Family history • Drug intake • Exposure to viral causes or prodromal symptoms (early non-specific symptoms) Initial investigations: • Pancreatic enzymes • Liver function tests • Ultrasound of gall bladder Subsequent investigations: • Fasting plasma lipids • Fasting plasma calcium • Viral antibody titres • Repeated biliary ultrasound • CT • MRCP (magnetic resonance cholangiopancreatoography) Further investigations: • Another ultrasound • EUS (endoscopic ultrasound) • ERCP (endoscopic retrograde cholangiopancreatography) – bile for crystal bile, pancreatic cytology, hepatopancreatic • Pancreatic function tests
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Determine severity of pancreatitis: Initial investigation 24 hr after admission Clinical impression of Clinical impression of severity severity APACHE II score >8 APACHE II score >8 BMI>30 Glasgow score 3 or more Pleural effusion on chest X- CRP>150 ray
48 hr after admission Clinical impression of severity APACHE II score >8 Glasgow score 3 or more CRP>150 Persisting organ failure
Biliary tract obstruction caused by a gallstone in the distal common bile duct. •
List the complications of acute and chronic pancreatitis
Complications of pancreatitis: • Multiple organ failure • Necrotising pancreatitis, abscess • Haemorrhage • Biliary complications • Pseudocyst Mortality of 10-15%. Management of acute pancreatitis: Support: IV fluid Respiratory Active monitoring ERCP: Severe attack due to gall stones Jaundice, cholangitis, dilated common bile duct Prophylactic antibiotics: • Conflicting evidence • Max 14 days FNA (fine needle aspiration): • When 30% necrosis • Less necrosis and sepsis Interventional radiology: • Embolisation for haemorrhage • Drainage of abscess Surgical: • Cholecystectomy during the same admission • Necrescetomy • Drainage of pseudocyst Management of chronic pancreatitis:
Suzie Rayner • Enzyme replacement • Adequate nutrition • Insulin supplement • Management of secondary complications (jaundice) In chronic relapsing cases: • Pain management • Rehabilitation of alcoholic patient • Surgical intervention (pancreatectomy) – for intractable pain that is not responsive otherwise, and management of secondary complication. _______________________________________________________________________ _
Alimentary System 5.1 – Organisation of the liver • • • • • • • • •
List the main functions of the liver Review the organisation of the liver and biliary system at the level of gross anatomy Describe the main features of the blood supply to the liver Explain the organisation of liver tissue in relation to its microcirculation, making correct use of the terms portal triad, central vein, sinusoidal capillary, hepatocyte, lobule, periportal region and centrilobular region Summarise the functional importance of the main structural features of hepatocytes (rough ER, Golgi complex, secretion granules, glycogen granules, mitochondria, smooth ER, junctional complexes) Draw a simple diagram outlining the relationships of hepatocytes to bile canaliculi and sinusoidal capillaries, and use this to explain major hepatic functions Define the position and main roles of the fixed macrophages (Kupffer cells) Outline the embryological origins of the liver Explain the main structural and functional changes in the liver between the embryonic period and the postnatal period
Liver and biliary system share a common origin with the ventral part of the pancreas at the beginning of the midgut. Liver has dual blood supply: • 20% arterial from hepatic artery • 80% is venous draining from the gut through portal vein Physiological importance: Lobule: unit of vascular supply, region of liver parenchyma surrounded by a ring of about 5/6 portal triads Liver in section appears to consist of lobules consisting themselves of:
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Cords of liver epithelial cells (actually sheets of hepatocytes), radiating from a central vein (draining via main hepatic veins to IVC) In centre of each lobule is a tributary of the hepatic veins, receiving blood draining from the sinusoidal capillaries.
Round the edges of adjoining lobules are: • Portal triads – consist of arteriole, branch of portal vein, bile duct. [enter together and retain this relationship throughout] • These all come from the main triad entering the liver at the porta or hilum • Hepatocyte nuclei – paler and rounded • Kupffer cells – phagocytic, flattened, dense cell nuclei [Note red cells in sinusoids between the hepatocyte sheets.]
• • •
Ignore the anatomical lobes based on the attachment of the mesenteries Boundary between territories of the L and R branches of hepatic artery is important. This puts the small lobes (caudate and quadrate) in with the functional L lobe.
Liver uses 2 pathways for secretion and absorption: • Secretion of bile from apical surface of hepatocytes through narrow canaliculi into the biliary ductules in triads. • Non-canalicular surface into or out of the blood sinusoids [perivascular space of Disse] (all transactions except bile) Main functions of the liver: Functions carried out by: • All roles carried out by hepatocytes(70% of mass) except for one • The exception to the rule is the breakdown and recycling of red cells, carried out by Kupffer cells (fixed macrophages) in the endothelial lining of the blood sinusoids.
Suzie Rayner Functions: • Secretes bile into duodenum (via gall bladder where bile is stored and concentrated) – bile is needed to emulsify dietary fats for efficient digestion and absorption • Phagocytose and break down over-date red cells • Excretes bile pigment (Hb breakdown products) into bile • Metabolises many natural and synthetic molecules to prepare them for excretion • Synthesises and secretes key blood proteins (albumin, fibrinogen) • Key site of insulin dependent glycogen storage and of intermediary metabolism of nutrients • Erythropoietin Hepatocyte surface: • Hepatocytes are arranged as complex, anastomosing sheets separated by wide sinusoidal capillaries. • Apical part of hepatocyte is reduced to a narrow band surrounding the cell, within the plane of the sheet of hepatocytes. • Tight junctions seal hepatocytes together to seal off bile calaliculi [in pre-term babies, these may leak bile pigment] • The apical domains bind a meshwork of bile canaliculi. • Only a very small part consists of bile canaliculus. • Most of surface faces other hepatocytes or • Space of Disse round the blood sinusoids. Bile canaliculi are a reduced ‘apical surface’ bounded by tight junctions. The basal surface faces the space of Disse and endothelium.
Space of Disse – separates the hepatocytes from the very thin, discontinuous endothelium of the sinusoidal capillaries.
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Schematically arrangement of hepatocytes and vessels can be done in several ways.
Liver Acini: • ‘Functional’ units • 100,000 per human liver • Each end at vascular stalk with terminal branches of portal vein, hepatic artery and bile duct • Blood flows in through portal vein and hepatic artery/arteriole • Blood flows outward to terminal hepatic venules in periphery.
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Alimentary system 5.2 – Liver functions Key roles in: • Digestion • Biosynthesis • Energy metabolism • Degradation/Detoxification Liver is: Large, multifunctional organ ‘Body’s kitchen’ Functions carefully regulated to meet body requirements Summary of cells and function: Liver as a Epithelial cells Kupffer cells whole Electrolyte Metabolic pool Phagocytosis
Bile duct system Bile drainage
Vascular system Sphincteric
Suzie Rayner and water balance Filter action Sponge action (blood volume regulation)
Storage
Blood pigment breakdown
blood flow regulation Sinusoidal permeability
Secretion – bile, glucose, protein, coagulation factors, enzymes Detoxification
• Briefly describe how the liver is supplied with blood [Mentioned in previous lecture] Hepatic blood flow – 25% of resting cardiac output Dual blood supply: • 20% from hepatic artery (L and R branches) • 80% from portal vein – drains gut, blood rich in nutrients must pass through liver. [Note: Lipids are mainly absorbed as chylomicrons into gut lymph rather than capillary blood] • Describe how the liver “buffers” the blood glucose concentration in terms of glycogen storage/breakdown and glucose synthesis from non-carbohydrate sources (gluconeogenesis) Role as blood glucose buffer: • Important to control blood glucose – endocrine course • After a meal, blood glucose increases, taken up by tissue • Stored as glycogen in muscle and liver (mainly) • Breakdown of liver glycogen maintains blood glucose concentration between meals • 24h fast will exhaust liver glycogen (80grams) After glycogen reserves exhausted, gluconeogenesis occurs : • From lactate → Pyruvate → glucose • From amino acids (via deamination) Alanine → Pyruvate → Glucose • From triglycerides, Glycerol → Glucose
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• Describe the role of liver in protein and fat metabolism. Protein metabolism: • Synthesis 90% plasma proteins – 15-50g/day • Plasma proteins are important as binding/carrier function, plasma COP – oedema • Synthesis of blood clotting factors • Synthesis of dietary ‘non-essential’ amino acids by transamination Transamination; • Synthesis of dietary ‘non-essential’ amino acids. Start with appropriate α-keto acid as precursor • Exchange amine group on one acid with ketone group on another acid. • Glutamic acid is common intermediate Essential amino acids do not have appropropriate keto acid precursors – therefore must be taken in via diet (lys, leu, ile, met, thr, tyr, val, phe) Deamination: • To use amino acids
as energy source they must be first deaminated • Conversion of amino acid into corresponding keto acid – remove amino group as ammonia • Occurs primarily on glutamic acid Examples
Urea synthesis: • Metabolism of NH2 leads formation NH3 • NH3 is toxic, therefore is converted to urea by liver • Urea – water soluble, metabolically inert, non-toxic
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Fat metabolism: • Fat is main energy store in body (100x that of glycogen) • Stored in adipose and liver • To metabolise, Fatty acids → Acetyl CoA (via acyl CoA and β oxidation) • Acetyl CoA is entered into krebs cycle • Alternatively 2Acetyl CoA → acetolacetic acid for transport in blood to other tissues where → acetyl coA → energy • Synthesise lipoproteins, cholesterol, phospholipids Lipoprotein synthesis: • Lipid transport problem in aqueous medium • Lipoproteins contain triglyceride, cholesterol, phospholipid and protein coat, which stabilizes the lipid. Lipoprotein types: VLDL – lots of triglycerides LDL – high cholesterol and phospholipid. Bad cholesterol → leads to atherosclerosis HDL – high protein content. Good cholesterol. Cholesteryl ester transfer protein (CETP) shuttles cholesterol from HDL → LDL. Therefore inhibiting CETP is in interest of drug companies. However stopped use due to: • Increased systolic blood pressure, deaths and cardiovascular events. Cholesterol – synthesis of sterol nucleus from acetyl coA (also in diet) – used in synthesis various compounds including steroid hormones and bile salts Phospholipid – fatty acid, phosphoric acid and nitrogen containing base Both phospholipid and cholesterol are important in structure of membranes of cells and intracellular organelles. •
Describe how bile is stored and concentrated in the gall bladder, and reabsorbed in the ileum, the main contents of bile and the role of bile in the digestion of fats. are bile salts, bilirubin, cholesterol, phosphlipids, bicarbonate ions and water Bile formation: • Continually secreted by liver • Stored and concentrated in gall bladder, holds 15-60ml • Concentrates bile salts Major components of bile: • Bile salts (50% dry weight) • Cholesterol • Phopholipids (lecithin) • Bile pigments (bilirubin, biliverdin) • Bicarbonate ions
Suzie Rayner • Water [Seperately, some components would be insoluble but together bile is stable.] Bile acids/salts: • Primary bile acids made from oxidation of cholesterol • This forms cholic and chenodeoxycholic acids – addition of carboxyl and hydroxyl groups so that the acids are water soluble • The acids are conjugated with glycine or taurine to produce secondary acids. • Further increases water solubility • Secondary bile salts are formed by bacteria in ileum de-conjugating and dehydroxylating primary bile salts 2 primary acids are formed, and converted by colonic bacteria into secondary acids: Cholic acid → deoxycholic acid Chenodeoxycholic acid → Lithocholic acid
Bile is secreted from apical surface of hepatocytes through narrow canaliculi into biliary ducts in triads. Bile salt molecule: • Steroid nucleus planar – 2 faces. Amphipathic • Hydrophobic – nucleus and methyl, face dissolves in fat • Hydrophilic – hydroxyl and carboxyl, face dissolves in water • Form micelles – released fatty acids and glycerol ‘wrapped’ by bile salts. • Detergent like properties make bile salt potentially cytotoxic in high conc., therefore cell membranes protected by: o Other intraluminal lipids
Suzie Rayner o Their own plasmalemma content of cholesterol and glycolipids
Bile functions: • Digestion/absorption of fat • Excretion of variety of substances via GI tract • Neutralise acid chyme from stomach Bile release: • Released in duodenum during digestion • Small amounts during cephalic and gastric phases due to vagal nerve and gastrin • Intestinal phase, CCK causes contraction of gall bladder, relaxation of heptopancreatic sphincter Digestion of lipids: Poorly soluble in water, therefore difficult to digest. Done in 4 stages in small intestine: Secretion of bile and lipases Emulsification Enzymatic hydrolysis of ester linkages Solubilisation of lipolytic products in bile salt micelles. Emulsification of lipids: • Water and fat don’t mix • Bile and lipases are secreted into the duodenum • Bile salts facilitate the emulsification of fat into suspension of lipid droplets • This increases surface area for digestion • Allows pancreatic lipase to split triglycerides into fatty acids and glycerol at fat/water interface Lipase: • Lipases break down triglycerides into monoglycerides and free fatty acids • Pancreatic lipase complexes with colipase which prevents bile salts from displacing lipase from fat droplet. Phospholipase A2: • Hydrolyses fatty acids at the 2 position in many phospholipids • Resulting in lysophospholipids and free fatty acids
Suzie Rayner Pancreatic cholesterol esterase: • Hydrolyses cholesterol ester to free cholesterol and fatty acid Absorption of lipids: • Micelles are absorbed much quicker than emulsion • Micelles allow transport across unstirred layer • Present fatty acids and monoglycerides to brush border • Whole micelle is not absorbed together: o Bile salts in Ileum o Lipid absorption usually complete by middle of jejunum • Bile salts are transported back to the liver for recycling Lipid metabolism: • Monoglycerides and free fatty acids absorbed by enterocytes are resynthesised into triglycerides by 2 pathways: o Monoglyceride acylation (major) – fatty acids bind to apical membrane, FA binding proteins facilitate transfer of FA from apical membrane → smooth ER. Here FA esterified into di-triglycerides o Phosphatidic acid pathway (minor) – triglycerides synthesised from CoA fatty acid and α-glycerophosphate Chylomicrons: • Lipoprotein particles synthesised in enterocytes as an emulsion • 80-90% triglycerides • 8-9% phospholipids • 2% cholesterol • 2% protein • trace carbohydrate • Chylomicrons are transported to the golgi and secreted across the basement membrane by exocytosis • Too big to enter blood capillaried so enter lacteals (lymph channels) instead. Enterohepatic circulation: • Active reabsorption bile salts in terminal ileum • De-conjugation and de-hydroxylation by bacteria make bile salt lipid soluble • Lose <5% per day • Recirculate bile via hepatic portal vein back to liver • Hepatocytes avidly extract bile salts, all cleared in one circulation • Bile salts are re-conjugated and some re-hydroxylated before re-use • Bile salt pool secreted 2x per meal.
Suzie Rayner
Detox and excretory functions of bile: • Liver breaks down steroid and peptide hormones, secreted into bile for excretion • Similar role for variety of ‘foreign compounds’ – drugs • Excretory route allows for excess cholesterol – lecithin allows more cholesterol into micelles • If too much cholesterol moves into micelles, gall stones. • Excretion of bile pigments • Bilirubin from breakdown of haem from old red blood cells (15% from other protein), iron from haem removed in spleen • Porphyrin group is reduced to bilirubin and conjugated to glucoronic acid in liver • Liver disease – bile pigment gallstones •
Define the term jaundice. Explain the difference between haemolytic and obstructive jaundice • Results from high concentration of bilirubin in extracellular fluid • Gives skin and sclera (eye) yellow tint Two types: Haemolytic – due to high rate of red cell destruction. Normal level of bilirubin, but overwhelmed. Obstructive – damage to liver cells or bile duct blockage. Rate of bilirubin production is normal, excretion is reduced. •
Briefly describe the role of the liver in metabolising/inactivating steroid and peptide hormones and various “foreign” chemicals (drugs) which are then excreted in bile, the storage of fat soluble vitamins (A,D,E,K), vitamin B12, iron (as ferritin)
Suzie Rayner
Larger functions of liver: • Store fat soluble vitamins (A,D,E,K) – store sufficient for 6-12 months except small vitamin K store. • Storage of iron as ferritin – available for erythropoeisis • Storage of vitamin 12 – pernicious anaemia, nerve demyelination • Glycogen and fat store •
Describe how Kupffer cells in liver sinusoids destroy any bacteria which have entered the blood from the gut lumen Protection: • Liver sinusoids contain Kupffer cells (tissue macrophages) • Kupffer cells prevent bacteria crossing from gut lumen → blood •
Describe how the liver performs the first hydroxylation step on vitamin D necessary to convert it to the biologically active form
Ca2+ metabolism: • UV light converts cholesterol to vitamin D precursor • Requires double hydroxylation to convert it to active • First in liver, then in kidneys • Without it, rickets.