The Burden of Alimentary Disease

Transcription

1 The Burden f Alimentary Disease Prfessr Mark Thursz (m.thursz@imperial.ac.uk) Organs f the gastrintestinal tract (GI tract) Muth + esphagus Stmach Small intestine (dudenum, jejunum + ileum) Liver Biliary system Pancreas Large intestine (cln, rectum + anus) Cln cnsists f caecum, appendix, ascending cln, hepatic flexure, transverse cln, splenic flexure, descending cln, sigmid cln Cmpnents f burden f disease (details n pp) Patient burden Epidemilgical statistics Incidence mre imprtant fr acute diseases Prevalence mre imprtant fr chrnic diseases Health ecnmic Mrbidity Mrtality QUALYs/DALYs Scietal burden Health Cst taxpayer vs individual Symptms f GI disease (examples n pp) Symptms are what the patient may cmplain f. They may be divided int general and reginal symptms. General (many GI diseases are difficult t diagnse specifically d t the frequency f general symptms) Anrexia Weight lss Anaemia Upper GI tract Haematemesis vmiting bld Melaena bld in stl Nausea Vmiting Dysphagia inability t swallw fd Odynphagia pain n swallwing Heartburn burning sensatin in epigastric regin that mves upwards Acid regurgitatin Belching Chest pain Epigastric pain pain in the epigastric regin (upper central regin abve TPP and between midclavicular lines Liver + Biliary system (majrity f liver disease des nt present with symptms until very advanced) Right upper quadrant pain Biliary clic term used t describe when biliary tree is bstructed by a gallstne abd pain 1

2 Icterus - jaundice Pruritus dark urine Chlestasis pale stl Ascites abdminal distensin; may be assciated with liver OR luminal GI tract disease Mid GI tract + pancreas Abdminal pain Diarrhea Steatrrhea abnrmal amunts f fat in the faeces, due t malabsrptin f fat in the gut Distentin abd swelling Lwer GI tract Abdminal pain Bleeding Cnstipatin Diarrhea Incntinence inapprpriate invluntary passing f urine, i.e. wetting yurself Signs f GI disease (n pp) Again, these may be divided generally and reginally General Cachexia a cnditin f abnrmally lw weight, weakness + general bdily decline Obesity Lymphadenpathy disease f the lymph ndes Anaemia Jaundice Stigmata f chrnic liver disease Hands Kilinychia the develpment f thin, brittle, cncave nails Leucnychia white discluratin f the nails Clubbing increased cnvexity f the nail fld, with assciated increased sftening and lss f the nrmal angle between the nail-bed and fld Dupytrens cntracture a flexin defrmity f the fingers (usually ring and little) with increased cntracture f the palmar fascia (think f wrk experience!! Saw this in surgery) Tachycardia tremr Abdmen Organ enlargement Mass Tenderness distensin Anus + rectum Haemrrhids enlargement f the nrmal spngy bld-filled cushins in the wall f the anus Fistula an abnrmal cmmunicatin (i.e. hle/pathyway) between tw hllw rgans/ne hllw rgan and the surface f the skin, i.e. an anal fistula is an pening between the anal canal and the surface f the skin Fissure a break in the skin lining the anal canal pain during bwel mvements and smetimes bleeding Rectal masses Prctitis inflammatin f the rectum 2

3 General Statistics abut GI diseases 5% UK adults suffer chrnic illness e.g. pancreatic, liver, inflammatry bwel disease Drug prescriptins > 4 billin Respnsible fr 12% UK deaths 1/8 hspital admissins ¼ main peratins Majr GI Diseases Wrldwide Malnutritin Enteric infectins Viral hepatitis + cnsequences Gastric cancer UK Dyspepsia Liver disease (due t alchl + besity) Cln cancer NB: Mrtality rates the mrtality rates f respiratry infectins, infectius diseases and circulatry-related diseases are all relatively decreasing. Mrtality rates f cancer are als stabilising. Hwever deaths frm liver-related diseases are increasing. 4-6% f UK ppulatin have abnrmal LFTs (liver functin tests). The main causes f these abnrmal LFTs include: Chrnic HepB Chrnic HepC Alchl-related steat-hepatitis (this is hugely increasing due t increasing alchl cnsumptin) Obesity-related steat-hepatitis GI Diseases Hepatitis HBV HCV 32nm virus 350 mil chrnically infected 1 mil deaths/yr Mst prevalent in nrthern suth America, Africa and Asia, and least prevalent in suthern suth America, UK and Australia hwever due t increasing UK immigratin, rates in the UK are rising Outcme f HBV infectin <1% fulminant infectin 90% self-limiting infectin 10% persistent infectin with 70% being asymptmatic and 30% having cirrhsis +/- hepatcellular carcinma Mst prevalent in inner cities Highly stigmatized as assciated with sexual transmissin Outcme f HCV infectin 20% self-limiting infectin 80% persistent infectin with 20% prgressive and 80% f cases being nn-prgressive Dyspepsia I.e. indigestin 3

4 Cmmn reasn fr primary/secndary cnsultatins High risk fr cmplicatins 40% prevalence in adults, with 26% experiencing symptms n a weekly basis but nly 2% cnsulting their GP 100 millin fr OTC medicatin Related t GORD (gastr-esphageal reflux disease) assciated with gastric reflux GORD may ptentially lead t the develpment f cmplicatins such as strictures (4-20%), esphageal ulceratin, bleeding + perfratin 2-7% f GORD patients will g n t develp an esphageal ulcer chrnic esphigitis Chrnic esphagitis is generally regarded as the primary cause f Barrett s esphagus, and the epithelial changes that ccur have been linked t a substantially increased risk f esphageal carcinma Barrett s esphagus ccurs in 10-15%, and results in epithelial changes in which the squamus-cell epithelium f the esphageal mucsa is replaced by metatastic clumnarcell (i.e. metaplasia ccurs) There is als an assciatin between symptmatic GORD and esphageal adencarcinma, independent f Barrett s esphagus The develpment f esphageal adencarcinma instead f esphageal carcinma is linked t an increased frequency, severity and duratin f GORD symptms Hwever the abslute risk f develping adencarcinma is still very lw (1/2 mil) Helicbacter pylri related Helicbacter pylri Gram-negative, spiral bacterium which clnises the gastric mucsa Infectin persists fr life unless treated Fund in 50% f the wrld s ppulatin gegraphic distributin is clsely linked sci-ecnmic develpment (i.e. in better sci-ecnmic develped cuntries decreased prevalence) Helicbacter related disease chrnic gastritis 85% n lng-term effects 14% peptic ulceratin 1% gastric adencarcinma/lymphma Dudenal ulcer caused by helicbacter pylri + NSAIDs Affects up t 10% f the ppulatin Estimated t cause up t 2000 UK deaths Main cmplicatin = perfratin + bleeding Cancer in the GI tract Prevalent in the UK: clrectal, esphageal, pancreatic, stmach + liver Liver cancer May be primary r secndary Primary liver cancer arise in liver cells, e.g. hepatcellular + chlangi carcinmas mre prevalent in assciatin with cirrhsis Secndary liver cancer is metastatic cancer frm ther primary lcatins; is mre cmmn in the UK but results in later detectin Primary liver cancer can be detected at an early stage by ultrasund scanning, with an assciated 50% 5 yr survival Chlangicarcinma n treatment Pancreatic cancer 4

5 95% adencarcinma f the pancreatic duct, which is difficult t diagnse early there has ne f the prest survival rates (2% at 5yrs) Inflammatry cnditins Ulceratic clitis + Crhn s disease UK prevalence 150,000 peple 8,500 new diagnsed cases/yr Ulceratic clitis nly affectsthe cln and rectum, and may have an acute presentatin; ulcerative chlitis with assciated txic megacln (rapid dilatin f the cln) Crhn s disease results in transmural inflammatin, structures and fissures at any part f the GI tract Celiac disease Cmmn in the west Prevalence f 1/1000 Caused by gluten sensitivity, with an HLA related aetilgy Results in subttal villi atrphi, with assciated malabsrptin Biliary diseases Gallstne prevalence 1/10 Mst prevalent in middle-aged verweight wmen Pancreatic diseases Acute pancreatitis Mid t life-threatening Blckage f the pancreatic duct results in a back-up f pancreatic enzymes causing severe inflammatin Ethanl accumulatin + gallstnes als present in 80% cases Chrnic pancreatitis Results in permanent damage t the pancreas, which may greatly impair quality f life Main cause alchlism Intestinal diseases Diarrhea prevalence wrldwide = 200 mil Water + fdbrne infectins caused by viruses, bacteria + parasites clean water supply essential! Large bwel diseases Irritable bwel syndrme (IBS) Affects 1/3 ppulatin Only abut 1 in 10 peple seek GP Anal diseases Faecal incntinence (siling) may affect 1/20 peple By age 50, abut ½ ppulatin have haemrrhids Over half f the >70yr ld ppulatin have diverticula f the large intestine Ecnmic burden f GI diseases Mrbidity England in-patient care GI diseases accunted fr 5.51 millin bed-days (6.1% f the ttal, 90 millin); equivalent t 1.36 billin p.a. Out-patient care 6.9% attributable t GI causes csts 0.28 billin p.a. 5

6 Primary care (GP visits) 3.85 % attributable t GI causes 0.24 billin p.a. Cmmunity health & scial services GI attributable in 3% 0.32 billin NHS prescriptin csts Classes f drug (BNF) Antacids Antispasmdics Ulcer-healing Chrnic diarrheal agents Laxatives Haemrrhid treatment Stma care Intestinal secretin drugs Ttal cst t NHS in 1995/6 was 0.83 billin NOTE: Other ecnmic factrs t cnsider include the cst f nt wrking, as well as further NHS csts (in-patients, ut-patients, primary care, drugs + cmmunity services) which have a cmbined cst f 8 billin 6

7 Intrductin t the small intestine the Dudenum, Jejunum and Ileum Alimentary System 2 - Dr Carline Small (c.small@imperial.ac.uk) 1. List the main functins f the small intestine. 2. Distinguish between the dudenum, jejunum and ileum. 3. Describe the nature f villi and crypts. 4. Describe the surce & prcess f entercyte renewal in the small intestine 5. Explain hw entercytes are adapted fr absrptin. 6. Cmpare turnver time f intestinal epithelium with epithelia frm ther sites. 7. Describe the structure/functin relatinship f the digestive epithelium. 8. Describe the structure/functin relatinship f the circular muscles. 9. Explain digestin and absrptin f carbhydrates, prteins and lipids in the small intestine. The small intestine can be sub-divided int three separate areas: the dudenum, jejunum and ileum. The primary functin f all three areas is absrptin f nutrients, salt and water (ie ingested substances) frm the lumen t the bld. Structure + Cell types Size: the small intestine is ~6m lng, with a 3.5cm diameter. The dudenum is ~25cm lng, jejunum=2.5m and ileum=3.75m. Basic rganisatin The mesentery surrunding the small intestine is flded, and has a large bld supply t supprt the metablic functins f the cells, as well as aid absrptin. There is n sudden transitin between the different areas; all have the same basic rganisatin but may have slightly different histlgical features. Digestive epithelium: lies n an external muscular wall (cnsisting f lngitudinal + circular muscles), with an internal circular-flded mucsa (cnsisting f different cell types). The mucsa are cvered in villi (~1mm tall increase surface area fr absrptin), with invaginatins knwn as crypts f lieberkuhn. Intestinal villi: can be classified as a simple epithelium (1 cell thick) cnsisting f clumnar absrptive cells (entercytes), with interspersed secretry cells (gblet cells) and enterendcrine cells The villi are mtile, have a large bld supply, gd lymphatic drainage and gd innervatin frm the submucsal plexus Between the villi, are crypts f lieberkuhn epithelium which include paneth cells and stem cells. Cell types Entercytes Mst abundant Tall clumnar cells with apical micrvilli, basally lcated nuclei Specialised fr absrptin frm the apical lumen t the basal bld supple They have a shrt life-span (1-6 days) therefre have a dynamic envirnment with a rapid cell turnver There are tight junctins between the cells imprtant fr intercellular cmmunicatin Micrvilli make up the brush brder verlaying the apical membrane f the entercytes (# micrmetres). There are several thusand micrvilli/cell thus greatly increasing the surface area fr absrptin. 7

8 Glyccalyx - rich carbhydrate layer lies n the apical membrane, serves as prtectin f bth the micrvilli and entercytes frm the digestive enzymes, yet prvides an envirnment in which efficient digestin can ccur. It traps a layer f water + mucus knwn as the unstirred layer many enxymes are present within this layer, thus it regulates the rate f absrptin frm the lumen NB: Surface area the the mucsal flds, villi and micrvilli act t increase the cylindrical internal surface area f the small intestine by 500x (frm m 2 ). This prvides the maximum pprtunity fr nutrient absrptin. Gblet cells 2 nd mst abundant epithelial cell type, cntaining mucus filled-granules which accumulate at the apical end (leading t the characteristic gblet shape). The plarity f the granule accumulatin als ensures secretin is unidirectinal (ie ges int lumen, and nt bld) Mucus large glycprtein that facilitates the passage f digested material thrugh the bwel The abundance f gblet cells increases alng the length f the small intestine, ie the dudenum cntains relatively few cmpared t the cln. Enterendcrine cells Again, these are clumnar epithelial cells which are scattered amng the absrptive cells In the intestine, these are mst cmmnly fund in the lwer parts f the crypts Hrmne-secreting cells (als knwn as chrmaffin cells) which influence gut mtility (see Regulatin f functin lecture) Paneth cells Are fund in the bases f the crypts Cntain large acidphilic granules The granules cntain the antibacterial enzyme lyszyme (which prtects the stem cells frm any bacterial pathgens), as well as glycprteins + zinc ( trace metal is essential fr functin f a number f enzymes) Als engulf sme bacteria and prtza, therefre may have a rle in regulating intestinal flra. Stem cells Entercytes and gblet cells have a shrt life-span, therefre cntinuus cell prliferatin, differentiatin + death ccurs (ie there is rapid turnver f cells) Pluriptent cells cntinually divide by mitsis and migrate t the apical membrane f the villus tip, where they are shed ff (regulated prcess by which the cells becme senescent ie they die and are slughed int the lumen) and digested 8

9 This rapid turnver prcess is cmmnly knwn as the escalatr f epithelial migratin, and acts as the first line f defence against GI pathgens, ensuring any infectins and lesins are shrt-lived. If the escalatrlike transit f entercytes is interrupted thrugh impaired prductin f new cells (e.g. radiatin), severe intestinal dysfunctin will ccur. E.g. f rapid epithelial turnver in defence against Chlera Link t water-transmissin established in 1854 by Jhn Snw The chlera entertxin results in a prlnged pening f the chlride channels in the small intestine allwing uncntrlled secretin f water int the lumen watery diarrhea This can lead t massive dehydratin and death It is treated with ORT t rehydrate the patient; hwever treatment against the bacterium is nt required as the bdy itself will expel the bacteria and entertxin via its rapid turnver when the epithelial cells are replaced. Differences in Histlgical Organisatin f the Dudenum, Jejunum + Ileum Dudenum distinguished by the presence f Brunner s glands which have alkaline secretins These are submucsal ciled tubular mucus glands which pen int the base f the crypts The alkaline secretins neutralise the acidic chime frm the stmach, prtecting the epithelium and prviding the ptimum ph fr the actin f pancreatic digestive enzymes Jejunum characterised by the presence f taller + thinner plicae circulars (als knwn as valves f Kerckring present in the dudenum + ileum, but as shrter and fatter) The jejunum als has a frilly interir frmed by the circular flds in the mucsa Ileum like the large intestine, the ileum has Peyer s patches (large clusters f lymph ndeules in the submucsa) These act t prime the immune system against intestinal bacteria and are well psitined t prevent bacteria frm the cln migrating up int the small intestine Mtility f the small intestine Functin f small intestine mtility: T neutralise the stmach chime and mix fd with the digestive secretins/enzymes T facilitate cntact between cntents f the intestine +intestinal mucsa T prpel intestinal cntents alng the alimentary tract Prcesses f small intestine mtility Segmentatin mixes the cntents f the lumen by frequent statinary cntractins f the circular muscles at intervals (With net mvement f cntents twards the cln) Peristalsis prpels chime twards the cln thrugh sequential cntractin f adjacent rings f smth muscle, with mst waves travelling abut 10cm Migrating mtr cmplex (rumbling stmach) waves f smth muscle cntractins which ccur predminantly during fasting (ccurs in less rdered/mre frequent fashin in fed state) that prevents the migratin f clnic bacteria int the ileum and cleans the intestine f residual fd. Each cycle begins in the stmach, and n reaching the terminal ileum, the cntractin f the adjacent segment begins in the dudenum. Digestin + Absrptin Digestin in the dudenum ccurs in an alkaline envirnment, and invlves digestive enzymes and bile which enter frm the pancreatic duct and bile duct respectively. The dudenal epithelium als prduces its wn digestive enzymes Digestin ccurs bth in the lumen, and in the unstirred layer f the membrane 9

10 There are 4 mechanisms f absrptin, which all ccur in the gut: passive diffusin, facilitated diffusin, primary active transprt and secndary active transprt. Type f Transprt Carrier Prteins Against/With Gradient Energy Required Passive Diffusin N With N Facilitated Diffusin Yes With N Primary Active Transprt Yes Against Yes (hydrlysis f ATP) Secndary Active Transprt Yes Against Yes (Electrchemical Gradient) Carbhydrates Cntain ~50% f ingested calries Digestin begins in the muth by salivary alpha-amylase, but this is destryed in the acid ph f the stmach. Mst digestin ccurs in the small intestine, primarily n the unstirred layer f membrane. Structure may be simple mnsaccharides (e.g. glucse + fructse) and disaccharides (sucrse + maltse), OR cmplex sugars bnded tgether t frm a chain (e.g. starch, cellulse + pectins) Pancreatic alpha-amylase secreted int the dudenum in respnse t a meal, requiring Cl- and slightly alkaline ph fr ptimum activity (prvided by Brunner s glands in dudenum) Absrptin different mechanisms are used fr different sugar mlecules: Glucse + galactse absrbed by secndary active transprt n carrier prtein SGLT-1 n apical membrane Fructse by facilitated diffusin n carrier prtein GLUT-5 n apical membrane GLUT-2 facilitates the exit at the baslateral membrane Prteins Digestin begins in the stmach by pepsin, which is then inactivated in the alkaline dudenum Pancreatic prteases are secreted int the small intestine as precursrs (e.g. trypsingen), which is then cnverted n the dudenal brush brder by enterkinase t trypsin. Trypsin then cntinues digestin and activates ther prteases invlved in digestin. Absrptin fllwing breakdwn f the prteins int large plypeptides, brush brder peptidases break dwn the peptides further int di/tri-peptides, and free amin acids. Free amin acids are then absrbed by facilitated diffusin and secndary active transprt Di/tri-peptides are absrbed using distinct carrier prteins, fllwed by breakdwn int amin acids by cytplasmic peptidases befre they crss the baslateral membrane Lipids Digestin f lipids in mre cmplicated, as they are prly sluble in water. It cnsists f a fur stage prcess in the small intestine: Secretin f bile + lipases Emulsificatin Enzymatic hydrlysis f ester linkages Slubilisatin f liplytic prducts in bile salt micelles 10

11 Emulsificatin required as lipids are prly water sluble; functin is t increase the surface area f the fat fr digestin Bile salts facilitate the emulsificatin int a suspensin f lipid drplets, which then allws pancreatic lipase t split triglycerides int tw fatty acids and a mnglyceride Bile salts mlecule is amphipathic; cnsist f a sterid-nucleus and bile acid hydrphbic face, and a hydrphilic face cnsisting f OH grups and carbxyl/sulfnic acid. The hydrphbic face disslves in fat, and the hydrphilic face disslves in water. Micelles bile salts frm micelles cnsisting f the hydrphilic head regins in cntact with the surrunding slvent, sequestering the hydrphbic tail regins f mnglycerides in the micelle cre. Pancreatic lipase initially breaks dwn triglycerides int mbglycerides and free fatty acids, as well as frming cmplexes with clipase; preventing bile salts frm displacing lipase frm the micelle. Other lipid enzymes phsphlipase A2 hydrlyses fatty acids at the 2 psitin in many phsphlipids, resulting in lys-phsphlipids and free fatty acids + pancreatic chlesterl esterase hydrlyses chlesterl ester t free chlesterl and fatty acids Absrptin micelles allw transprt acrss the unstirred layer, and present the fatty acids + mnglycerides t the brush brder The whle micelle is nt absrbed tgether; the bile salts are absrbed in the ileum, but lipid absrptin is cmplete by mid-jejunum Bile-salts are then transprted back t the liver fr recycling, thrugh the enterhepatic circulatin Lipid metablism invlves the re-synthesis f triglycerides in entercytes by tw pathways: Mntglyceride acylatin (majr) fatty acids bind t the epical membrane, where fatty acid binding prteins (FABP) facilitate their transfer t the smth ER (where they are esterified int triglycerides) Phsphatidic acid (minr) triglycerides are synthesised frm CA fatty acid and alphaglycerphsphate Chylmicrns after the re-synthesis f triglycerides in the entercytes, lipprtein particles are synthesised as an emulsin. These cnsist f 80-90% triglycerides, 8-9% phsphlipids, 2% chlesterl, 2% prtein and trace carbhydrate These are transprted t the glgi and secreted acrss the basement membrane by excytsis, where they enter lacteals (lymph channels) instead f bld vessels due t their large size Nte: the ileum is separated frm the cln by the ilecaecal sphincter. Relaxatin and cntractin f this sphincter cntrls the passage f material int the cln, as well as preventing the backflw f bacteria int the ileum 11

12 Malnutritin I Undernutritin Dr Gary Frst (g.frst@imperial.ac.uk) 1. Demnstrate a basic understanding f the rle f nutritin in health and disease 2. Demnstrate a basic understanding f the rle f gastrintestinal tract in maintaining nutritinal status 3. Have a basic understanding f the rle f the macr-nutrients in health and disease Intrductin t malnutritin There are tw extreme ends f malnutritin: under nutritin + besity The gut acts as a barrier that allws the mvement f nutrients acrss it. It is highly adapted fr this functin, and mst nutrients are efficiently absrbed in the small intestine (therefre states f malabsrptin have disastrus effects n bwel functin) Undernutritin results frm inadequate cnsumptin, pr absrptin, r excessive lss f nutrients Malnutritin mst cmmnly refers t undernutritin, but the term can als encmpass vernutritin (leading t besity); results frm vereating r excessive intake f specific nutrients. Malnutritin pses a majr health prblem: 1/3 glbal ppulatin live belw the recmmended nutritinal needs (1200kcal) 25% f western sciety is bese, which accunts fr mst f T2DM, 30-40% f CVD + is a large risk factr fr many cancers Maslw s Heirarchy f Needs Scial/psychlgical way f ranking things that are imprtant fr human survival; represented as a pyramid which illustrates the five levels f human needs. The mst basic needs are physilgical + safety/security, which are shwn at the base f the pyramid The bilgical systems f the bdy will NOT perfrm withut meeting nutritinal needs (water + fd base f the pyramid), therefre adequate nutritin is vital fr human survival NB: malnutritin is als assciated with a reductin in life expectancy (bth undernutritin during childhd and besity/vernutritin in adulthd) Malnutritin thus frms a dual prblem, which exists side-by-side Nutritin: the basics BMI (bdy mass index) Way f assessing bdy cmpsitin, in rder t estimate adipsity BMI = Weight (kg) / height (m) Als cnsiders waist measurement 12

13 Cnsiders 5 ranges, with a desirable range f (healthy weight) BMI is mre imprtant in cnsidering besity/verweight, as besity leads t increased risk in many diseases including all cancers (except melanma + bladder cancer) BMI less relevant when cnsidering patients wh are undernurished; severely undernurished patients may have a fluid imbalance, which will result in an inaccurate weight measurement Arm circumference and crrespnding arm skin-flds are used as surrgate measurements fr undernurished patients When cnsidering children, grwth and weight develpment charts are used Dietary reference values Estimate the nutritinal needs f a ppulatin, therefre can be used clinically t assess nutritinal adequacy Values based n the nrmal distributin f requirements fr different peple needed t maintain health and reduce the risk f diet-related diseases The amunt f each nutrient is called the nutritinal requirement, and may vary between individuals (and different life-stages) and fr each nutrient Dietary recmmendatins are based n the estimated average requirement, which cnsiders the intake: Need in rder t maintain circulating levels r tissue cncentratin Assciated with the absence f disease Need t maintain balance T cure sign f deficiency Assciated with an apprpriate bichemical marker f adequacy Nutrient requirements = the amunt which must be cnsumed by an individual t maintain ptimal health and functin/avid deficiency Must take int accunt the variatin between individuals in the nutrient requirements Must als cnsider the efficiency f utilisatin f the nutrient, e.g. nly 20% f irn is absrbed Methds used t determine the requirements include: Observatin f intakes Balance studies Physilgical estimates Clinical studies Functinal tests 3 reference values are cnsidered fr each nutrient (pltted n a nrmal distributin curve) Estimated average intake(ear) = mean requirement Lwer reference nutrient intake (LRNI) = 2.5 SD belw EAR (Upper) reference nutrient intake (RNI) = 2.5 abve EAR E.g. Vitamin C Ascrbic acid (Vit C) is an essential vitamin, with antixidant rles + imprtant in the frmatin f cllagen Deficiency in Vitamin C = Scurvy The dietary reference valure fr vitamin C (mg/day) increases with age (frm 15 at 0-6 mnths 25 at years) The link between Vitamin C and scurvy (i.e. the discvery f the treatment) can be cnsidered t be the first systematic trial (James Lind) Invlved 12 sailrs suffering frm scurvy, wh were segregated and treated with either cider, seawater, garlic mustand + hrseradish, vinegar, and rganges/lemns Thse fed citrus fruits experienced a remarkable recvery (ther 5 grups; 2/ garlic, died) 13

14 Energy Befre cnsidering nutrient requirements, the bdies demand fr energy in rder t meet metablic needs must be cnsidered If this is nt met, nutrients are nt used effectively, but rather are used t meet energy demands Energy demands - based n the 1 st law f thermdynamics (energy cannt be created nr destryed) Thus when weight is stable, energy in = energy ut + energy stred Weight gain, energy in > energy ut Increased intake Decreased expenditure Decreased metablic rate Energy ut can be divided int 3 cmpnents: Adaptive thermgenesis Physical activity Obligatry energy expenditure (BMR) Energy intake made up f fat, carbhydrates, prtein + alchl The estimated average requirements fr energy depend n sex + age The cmpsitin f the energy is als imprtant, i.e. there are specific dietary reference values fr prtein, carbhydrate + fat 14

15 Energy metablism all centred arund acetyl CA, and its pssible fates which adapt t nutritinal status; in a gd nutritinal state, Acetyl CA enters the TCA cycle. In a starved state, ketne bdy prductin is mre prevalent. Energy stre Glycgen stred in the liver +muscle (shrt term stre) Adipse tissue majr stre (lng term) Muscle tissue stre used during prlnged starvatin NB: there is an xidatin hierarchy f macrnutrient balance, which leads t fat sparing. This is due t the fact that with alchl, carbhydrate + prtein intake, there is an autmatic adjustment f xidatin which des nt ccur after intake f fat. Bdy cmpsitin (e.g. 70kg man) Shuld be: 42kg water 12kg fat 12kg prtein Glycgen, phsphates, ins + ther make up remaining mass Imprtance f bdy cmpsitin dictates: Energy expenditure Respnse t disease Risks t many chrnic diseases Sprting ability Grwth The human bdy increases in weight apprx. 20-fld frm baby-adult All the material in this weight gain enters the human bdy as fd, therefre yu are effectively what yu eat! Grssly abnrmal diets will cause changes in bdy weight, cnfiguratin + cmpsitin Age bdy cmpsitin will change dramatically frm fetus t adult: 15

16 NOTE: Ageing There are als assciated changes that ccur with aging: Decline in bdy size Increase in bdy fat Decline in muscle mass Decline in ttal bdy water Decline in liver mass Effects n required drug dsages + txicity f drugs Can ften lead t a dwnward spiral int undernutritin (mre cmmnly knwn as malnutritin) Regulatin f feeding Average human eats ~900,000kcals/yr 3% errr 27,000 calrie change 10lb weight change (hwever this des NOT happen) Feeding is nt just under vluntary cntrl, als under cntrl frm peripheral signals t the hypthalamus: Leptin, Ghrelin, PYY 3-36 PYY 3-36 = GI hrmne with anrexic effect Undernutritin Ghrelin = stmach + pancreatic hrmne with rexigenic effect Leptin = lng term regulatry hrmne released frm adipcytes with anrexic effect Leptin thrugh t be treatment fr besity, but besity increased leptin resistance therefre nt effective therapy Leptin is respnsible fr the additinal crdinated effects f under nutritin e.g. cessatin f menstrual cycles Causes In the develping wrld Plitics Climate Pr water Pr agricultural plicy Demand f the develped wrld Often in develped cuntries, the variety f fds is generally wrse, prviding less energy and wrse nutritin In the develped wrld Age Change in scial circumstances, e.g. islatin, death f partner + pr husing Illness Aging 10% f free living elderly peple are undernurished t a degree with impaired functin Specific nutrient deficiencies BERIBERI caused by Thiamine (Vitamine B1 derivative) deficiency Thiamine Occurs in the bdy as free thiamine + varius phsphrylated frms: mnphsphate (TMP), triphsphate (TTP) + pyrphsphate (TPP) Critical fr the release + utilisatin f energy frm fd (invlved in the breakdwn f energy mlecules e.g. glucse) + nerve functin (fund n neurn membranes) Occurs naturally in unrefined cereals + fresh fds (especially whle grain bread, fresh meat, legumes, green vegetables, fruit + milk) Beriberi Ailment f nervus system Symptms include sever lethargy + fatigue Cmplicatins affect cardivascular, nervus, muscular + GI systems 16

17 May be fund in peple whse diet cnsists mainly f plished white rice (thiamine-bearing husk remved) Prevalent in chrnic alchlics with inadequate diet (Wernicke-Krsakff syndrme) + pst gastric-bypass patients PELLAGRA caused by Niacin (vitamin B3 derivative synthesised frm trptphan) deficiency Niacin Nictinamide is the dericative f niacin and is used by the bdy t frm cenzymes: nictinamid adenine dinucletide (NAD) nictinamide adenine dinucletide phsphate (NADP) niacin cenzymes required Pallagra Initially thught t be an infectius disease Nted that appreared after staple crp was replaced by maize Cmplicatins (relating t lss f lean bdy mass) Lean Bdy Mass (% lss f ttal) Cmplicatins (related t lst LBM) Assciated mrtality (%) 10 Impaired immunity, increased infectin Decreased healing, weakness, infectin T weak t sit, pressure sres, pneumnia, n healing Death, usually frm pneumnia 100 Childhd malnutritin Decreases fat mass (therefre energy stres) Increase in water, decrease in nitrgen (prtein cmpsitin may remain cnstant) Delays in chemical maturatin Delays develpment Can affect IQ Starvatin Ketnes begin t supply energy t brain as free amin acids decline Bdy begins energy cnservatin measures Brain still dependant n glucse, therefre glucnegenesis must ccur (frm prtein catablism) Signs f undernutritin Weight lss Lss f subcutaneus fat (lse skin n extremities) Muscle wasting Peripheral edema (n cardiac disease) Glssitis, cracking edges f muth Hair lss 17

18 Chrnic infectins Pr wund healing, chrnic wunds, pressure sres Listless, apathetic Recurrent pulmnary infectins Adaptins t weight lss In respnse t energy restrictin/starvatin, the RMR (resting metablic rate) is reduced by bth passive and active methds Passive respnse t negative energy balance (hrmnal) Decrease insulin Decreased thyrxine decreased T3 Glucagn release Grwth hrmne release Leads t substrate mbilisatin f free fatty acids and amin acids weight lss + change in bdy cmpsitin Active respnse t reduced energy flux Decrease SNS activity Increase catechlamine prductin Leads t decreased metablic flux + energy expenditure decrease in metablic activity f the FFM (fat-free mass i.e. ttal bdy mass fat mass) Shrt fasts lead t a lss f glycgen + assciated water in liver, as well as lss f gut weight (water lss) Lng fasts prtect further liver + gut lss, therefre result in muscle and fat lss Nrmal Metablism Metablic rate 25-30kcal/kg/d Hrmnes balanced Intact skin prevents heat + water lss Energy prductin fr cell functin, muscle functin + tissue repair 50-60% kcal = Carbhydrate (xygen pathway t energy used) 25-30% kcal = Fat (used as micrnutrients) 5-10% kcal = Prtein (pathway t prtein synthesis used) Energy prductin used in lean mass cmpartment + fat mass dept Lean mass cmpartment; invlved in maintaining physical + metablic machinery (with anablic + catablic stimuli) Metablic Respnse t starvatin (shrt term) 18

19 The pancreas structure & functin Alimentary system 4 - Dr Kevin Murphy (k.g.mrphy@imperial.ac.uk) 1. Distinguish between the excrine + endcrine parts f the pancreas in structural + functinal terms 2. Review the anatmical regins and main relatins f the pancreas 3. Sketch the duct system f the pancreas 4. Define a pancreatic acinus 5. Describe the subcellular rganisatin f synthesis and secretin by the pancreatic acinar cells 6. Outline the embrynic develpment f the pancreas 7. List the mst imprtant cmpnents f the pancreatic (excrine) secretins + define their rles in digestin 8. Explain the mechanism fr bicarbnate secretin in terms f in exchange pumps + membrane in channels and the dependence n active transprt 9. Understand that acinar cells synthesise enzymes fr the digestin f carbhydrate, lipids and prteins + stre these in an inactive frm in zymgen granules, and explain hw these enzymes are activated when they enter the dudenum 10. Explain hw nervus stimulatin and the hrmnes secretin + CCK regulate the release f pancreatic juice Lecture utline: pancreatic develpment, endcrine + excrine rles, pancreatic juice, cntrl f secretin, stimulus interactin Pancreatic develpment Pancreatic buds grw ut int drsal + ventral mesenteries f fregut at junctin with midgut The ventral bud is part f the hepatbiliary bud The drsal bud then expands n the left t frm the head-neck-bdy-tail f the pancreas Islets f Langerhans are mst abundant in the tail f the pancreas The dudenum then rtate t frm a C-shape; the ventral bud then swings psterirly t the dudenum t fuse with the drsal bud, frming the rest f the head + uncinate prcess f the pancreas In sme peple, the tw ducts remain separate The ventral duct then usually acquires drainage frm the neck-bdy-tail f the pancreas t frm the main pancreatic duct, which pens int the cmmn bile duct just prir t entrance int the dudenum Structure Can be divided int 5 regins: tail, bdy, neck, head, uncinate (hk-like structure) Lies mainly n the psterir abdminal wall extending frm the C-shaped dudenum t the hilum f the spleen Pancreatic juice reaches the dudenum via main + accessry pancreatic ducts, which fuse with the cmmn bile duct and enter int the 2 part f the dudenum The branches f the duct system f bth the ventral and drsal buds five rise t bth excrine (Acinar) and endcrine (islets) tissue Anatmical relatins Lies psterir t the dudenum, and anterir t the IVC and arta Spleen lies supralaterally t the left, with the left and right kidneys psterlaterally n either side (each assciated with their wn adrenal gland) Als has clse relatins with (and supply frm) the celiac + superir mesenteric arteries NB: Imaging MRI scans can be used fr imaging f pancreatic tumurs, whereas angigraphy is mre cmmnly used fr assessing pancreatic disease 19

20 Endcrine + excrine rles f the pancreas Endcrine: secretin f substances int the bldstream t have effect n distant target rgans invlves ductless glands Excrine: secretin int a duct t have direct lcal effect The pancreas has 2 functinal parts: endcrine and excrine The endcrine functin f the pancreas makes up 2% f the gland; the islets f Langehans The islets are highly vascular, ensuring that all endcrine cells have clse access t a site fr secretin Excrine functin makes up the remaining 98%: acini; invlved in the digestive functin f the pancreas; secretes pancreatic juices int the dudenum - Pancreatic juices are rich in digestive enzymes and HCO 3 Endcrine secretins f the pancreas are frm the islets f Langerhans, which cnsist f 3 different cells; each f which secrete a different hrmne: Beta cells (~60-80% f tissue) secrete insulin: anablic hrmne which prmtes glucse transprt int cells + strage as glycgen thus reduces bld glucse, prmtes prtein synthesis + lipgenesis Alpha cells (~15-20% f tissue) secret glucagn: hrmne which increases glucnegenesis + glycgenlysis (thus increases bld glucse) Delta cells (@5-10% f tissue) secrete smatstatin: regulatry hrmne which acts as endcrine cyanide Pancreatic disease may invlve bth excrine + endcrine effects, e.g. cystic fibrsis Pancreatic cell differentiatin Acinar cells frm grape-like spheridal clusters f 10+ secretry epithelial units which secrete pr-enzymes int ducts The enzyme precursr prteins are synthesised n RERE, glycsylated srted + packed in the Glgi cmplex, stred in secretry granules + secreted by apical excytsis The endcrine cells f the pancreas are derived frm the branching duct system (predminantly in the tail f the pancreas), but eventually lse cntact with the ducts t frm separate islets and then different further t specialise int the different cell types Between the excrine acini and endcrine islets are sepat f cnnective tissue, with clumnar epithelium lining the interspersed minr pancreatic duct, which fuse t frm the majr pancreatic duct Pancreatic juice There are 2 cmpnents f pancreatic juice: Lw vlume, viscus slutin rich in digestive enzymes secreted by acinar cells High vlume, water slutin rich in HCO secreted by the centracinar cells + duct cells Acinar cells are large with apical secretry granules These granules stre the inactive precursrs in rder t prtect the tissue frm aut-digestin Duct cells are small, pale, with few granules Bicarbnate secretin Cncentratin 120mM ph Functin: neutralises acid chime frm the stmach (preventing damage t the dudenal mucse + prviding the ptimum range fr pancreatic enzymes The bicarbnate secretin washes the lw vlume secretin ut f the pancreas int the dudenum 20

21 Effect f dudenal ph n bicarbnate secretin rate (seen in graph) When dudenal ph<5, there is a significant linear increase in pancreatic bicarbnate secretin When dudenal ph<3, there is nt much mre increase in the bicarbnate secretin The reasn that bicarbnate secretin stps even thugh the ph is still acidic is due t bile + Brunners glands in the dudenum Bile als cntains bicarbnate + helps neutralise the acid chime Brunners glands (see small intestine lecture) als secretes alkaline fluid Mechanism f secretin 1. Separatin f H + and HCO Catalysed by carbnic anhydrase - CO 2 diffuses int the duct cell frm the bld, reacting with H 2 O t frm H + + HCO 3 - CO 2 + H 2 O H + + HCO Simultaneusly, Na + mves dwn a cncentratin gradient between tight junctins (paracellular transprt), and H2O fllws 2. Transprt f H + + HCO 3 - ut f the duct cell cupled exchange driven by electrchemical gradients (secndary active transprt) - The HCO 3 - is exchanged with Cl -, which has a high lumen cncentratin cmpared t IC duct cell cnc, therefre the bicarbnate is transprted int the lumen, with Chlride ging int the cell - H + is exchanged with Na +, which has a higher bld cnc cmpared with the cell cnc, thus flws int the cell and H + thus is transprted int the bld 3. Maintenance f the Na + gradient Primary active transprt using ATP - In rder t exchange H + fr Na in step 2, the Na+ gradient needs t be maintained. This is dne using the Na/K exchange pump 4. Returning f the K + (t the bld) and Cl - (t the duct cell) - via prtein channels NOTE: the same reactin CO 2 + H 2 O H + + HCO - 3 ccurs in gastric parietal cells + pancreatic duct cells In the stmach, the hydrgen ges int gastric juice and the bicarbnate int bld In the pancreas, the bicarbnate is secreted int the juice and the hydrgen int the bld Enzyme secretin Lipases, prteases + amylases are synthesised and stred in zymgen granules Zymgens are pr-enzymes This prtects the acini + ducts frm autdigestin Clinical crrelate: acute pancreatitis blckage f pancreatic duct may verlad this prtectin and result in aut-digestin f the pancreas Digestin f prteins Prtein digestin is started in the stmach by pepsin, which acts in acid cnditins When chime enters the dudenum, the pepsin that is mixed int it cmes as well, but is sn inactivated by the alkaline cnditins 21

22 The pancreas prduces a ccktail f prteases, all released as precursrs e.g. trypsingen (which is then activated t frm trypsin) The pancreas cntains a trypsin inhibitr t prevent trypsin activatin f prteases, therefre ensuring the enzymes are nly activated in the dudenum The dudenal brush brder prduces enterkines, which cleaves the trypsingen between a valine + an isleucine. Trypsin can then g n t activate ther prteases in the same way. All the prteases are fairly shrt lives as they are digested themselves NB: trypsin als cnverts sme liplytic enzymes, but als requires clipase + the actin f bile salts fr effective actin Altered pancreatic enzyme functin Pancreatic secretins adapt t diet, e.g. high prtein, lw carb Pancreatic enzymes are essential fr nrmal digestin Lack f these can lead t malnutritin, even if the dietary input is k ORLISTAT (anti-besity drug) inhibits pancreatic lipases Steatrrhea increased faecal fat by reducing intestinal fat absrptin Als ccurs e.g. during cystic fibrsis + chrnic pancreatitis Cntrl f pancreatic secretin Pancreatic secretin begins befre fd enter the dudenum via a vagal reflex in respnse t the smell/taste f fd this is knwn as the CEPHALIC PHASE, invlving chlinergic synapses which nly result in enzymatic secretin When fd arrives in the stmach, the GASTRIC PHASE is stimulated. This invlves the same mechanisms as the cephalic phase INTESTINAL PHASE - When acid chime enters the dudenum frm the stmach, it stimulates the dudenal mucsa t release hrmnes (secretin + CCK: chlecystkinin) int the bld This is respnsible fr f pancreatic secretin, and stimulates bth cmpnents f pancreatic juice Secretin is released by the acid ph and stimulates bicarbnate secretin Invlves camp CCK is released in respnse t fats/prteins + stimulates enzyme secretin Invlves Ca 2+ and PLC via vagus reflex The cephalic phase ends when meal is eaten Ansrptin f fats and peptides remves the lcal luminal stimulus fr CCK release, thus ending the intestinal phase Stimulus interactin There is a synergistic interactin between CCK + secretin, i.e. CCK cmbined with secretin shws a marked increase in bicarbnate secretin cmpared t secretin alne. Summary (what happens during a meal) Fd mixed, digested in stmach, ph 2 Chyme squirted int dudenum H+ ins in dudenum stimulate release f secretin, stimulating release f pancreatic juice (plus bile and Brunner s gland secretins) t raise ph t neutral/alkaline. Peptides + fat in dudenum cause sharp rise in CCK, vagal nerve, stimulating pancreatic enzyme release, peaks by 30 mins, cntinues until stmach empty. CCK ptentiates effects f secretin n aqueus cmpnent (necessary because mst f dudenum nt at lw ph). 22

23 Bile, bilirubin & jaundice Alimentary system 5 - Shahid A Khan (s.khan@imperial.ac.uk) 1. Understand the prductin + excretin f bilirubin 2. Describe the features f pre-hepatic, hepatic + pst-hepatic jaundice 3. Give tw examples f each f these types f jaundice 4. Describe the pathgenesis f the symptms + signs assciated with jaundice Lecture structure: bile cmpsitin/prductin, bile salts, anatmy f the biliary system, regulatin f bile flw + secretin, gall bladder functin, cntrl f flw, bilirubin metablism, jaundice Bile Why d we prduce bile? Bile has 3 imprtant rles: Chlesterl hmestasis Dietary lipid/vitamin absrptin Remval f xenbitics/drugs/endgenus waste prducts E.g. chlesterl metablites, adrencrtical, ther sterid hrmnes Xenbitics exgenus cmpunds e.g. fd additives, which we are expsed t Cmpsitin f bile Water, bile salts, inrganic salts, bile pigments (bilirubin, bilivirden), fatty acids, lethicin, fat, chlesterl, alkaline phsphatase, drug metablites + trace metals All cmpnents frm an alkaline electrlyte slutin There are als ther substances excreted int bile: Andrencrtical + ther sterid hrmnes Drugs/xenbitics Chlesterl Alkaline phsphatase (ALP) Clinical crrelatin: in duct bstructin, there is an increase in chlesterl + ALP, which may result in jaundice. Hwever in hepatic illness, the increase is NOT in ALP, but rather ALT + AST (alanine transaminase + aspartate transaminase) The glden-yellw clur f bile is due t glucnrides f bile pigments Prductin f bile The liver is mainly made up f hepatcytes, with an intersperse biliary tree (duct system) lined by chlangicytes ml prduced + secreted daily 60% by hepatcytes 40% by chlangicytes The bile drains frm the liver int the dudenum at the dudenal papilla Rle f the biliary tree: The biliary epithelium is imprtant in altering the ph + fluidity f bile. It mdifies the bile as it flws thrugh it. This includes: Splitting f glutathine int cnstituent amin acids (which are reabsrbed) Reabsrptin f glucse + sme rganic amin acids Cntributin f IgA frm chlangicytes by excytsis CFTR mechanism (cystic fibrsis transmembrane regulatr) actively secretes bicarbnate and chlride ins int bile 23

24 Clinical crrelatin: mutatin in CFTR gene in cystic fibrsis reductin in this mechanism cntributing t liver cirrhsis + fibrsis Water is als drawn intp bile by smsis thrugh paracellular junctins Bile flw Is clsely related t the cncentratin f bile acids + salts in the bld Bile salts Biliary excretin f bile salts is perfrmed by transprters expressed n the apical surface f hepatcytes and chlangicytes, which gvern the rate f bile flw as well Dynsfunctin f the transprters is a majr cause f chlestasis stasis f the biliary tree/bile duct which may lead t jaundice The main transprters include: Bile salt excretry pump (BSEP) respnsible fr the active transprt f bile acids acrss hepatcytes int bile MDR related prteins (MRP1 + 3) - Prducts f the familial intrahepatic chlestasis gene (FIC1) Multidrug resistance genes (MDR1 +3) MDR1 mediates the canalicular excretin f xenbitics + cyttxins int bile MDR3 encdes a phsphlipid transprter prtein that translcates phsphatidylchline frm the inner t uter leaflet f the membrane Bile salts are sdium + ptassium salts f bile acids cnjugated t glycine + taurine Bile acids are synthesis frm chlesterl; 4 acids in humans 2 primary acids are frmed in the liver: Chlic acid Chendexychlic acid These are then cnverted by clnic bacteria: Chlic acid dexychlic acid Chendexychlic acid lithchlic acid The prupse f the cnjugatin is t make the initial cmpunds mre easily absrbed + metablised Functin Fats are water insluble, and bile cnsists f predminantly water, therefre bile salts allw emulsin f the lipids in the water by reducing the surface tensin f the fat and frming micelles in the water They are able t d this by frming micelles due t their amphipathic nature they frm a lipid hydrphbic cre with a hydrphilic surface allwing the lipids t be transprted t the GI tract epithelial cells fr absrptin The detergent-like actins make bile salts ptentially cyttxic in high cncentratins, but cell membranes are prtected by ther intraluminal lipids and their wn membrane cntent f chlesterl + glyclipids. Hwever they are thught t cntribute t liver cancer at very high cncentratins. The biliary system Anatmy Hepatcytes are the majr functinal cells f the liver, which frm cmplex 3D arrangements called hepatic laminae (1 cell thick layers) 24

25 Bile canaliculi are small ducts between hepatcytes that cllect bile + drain int bile ductules bile ducts and eventually the cmmn hepatic duct. Hepatic sinusids are highly permeable bld capillaries that receive xygenated bld frm branches f the hepatic artery + nutrient-rich dexygenated bld frm branches f the hepatic prtal vein. At a transit time f ~8.4s, these cnverge and deliver bld int a central vein, which flws int the hepatic vein which drains int the IVC A bile duct, branch f the hepatic artery + branch f the hepatic vein tgether are referred t as a prtal triad. The hepatcytes, bile duct system + hepatic sinusids can be rganised int units called hepatic lbules: hexagnal structure with a central vein with radiating hepatic laminae + sinusids. At the three crners f the hexagn is a prtal triad. Hepatcytes at the extreme periprtal zne (i.e. clsest t the prtal triads) make cntact with the chlangicytes lining the bile ducts. Here, there is a shrt stretch where bile flws in channels lined by bth chlangicytes + hepatcytes = Canal f Hering The liver can als be rganised int functinal units called acini: Each hepatic acinus is an apprximately val mass that includes prtins f tw hepatic lbules The shrt axis f the hepatic acinus is defined by the branches f the prtal trias, that runs alng the brder f the hepatic lbules (i.e. marked by the brder where the 2 lbules meet) The lng axis is tw imaginary curved lines which jin the tw central veins The hepatcytes are then arranged in 3 znes arund the shrt axis Zne 1 are first t receive incming xygen, nutrients + txins frm the bld, thus are last t die if circulatin is impaired Bld flws utwards Zne 3 are last t receive incming xygen etc, and t shw effects f bile bstructin Regulatin f bile flw & secretin The right lbe f the liver drains int the right hepatic duct The left lbe f the liver drains int the left hepatic duct The R + L hepatic ducts calesce just utside the liver t frm the hepatic duct The Gall bladder has cystic duct, thrugh which stred bile is released which needed fr digestin The cystic duct + hepatic duct fuse t frm the cmmn bile duct, which lies psterir t the pancreas and pens int the dudenum at the ampulla f vater (cntrlled by the sphincter f Oddi) Between meals, bile is stred in the gall bladder as the sphincter f Oddi is clsed Eating causes the sphincter f Oddi t relax, and release f GI mucsal hrmne CCK gall bladder cntractin + secretin f bile Enterhepatic circulatin Liver cells transfer varius substances frm plasma t bile; many f which are then cncentrate in bile e.g. glucnuride, which is hydrlysed then reabsrbed int the circulatin i.e. the cycle repeats itself 25

26 This can prlng the actin f different drugs, e.g. mrphine Summary = GI tract prtal bld uptake by hepatcyte + excretin int canaliculus bile duct GI tract reabsrptin int terminal ileum + transprt ut f entercytes Circulatin f bile salts Bile salts enter the dudenum, are transprted thrugh the jejunum int the ileum 95% are then absrbed frm the ileum + enter the enterhepatic circulatin t return t the liver 5% are cnverted t secndary bile acids in the cln, with dexychlate being absrbed int the venus circulatin t the liver + lithchlate being excreted 3.5 grams f the bile salts recirulate in enterhepatic circulatin Clinical crrelatins w/ enterhepatic circulatin Terminal ileal resectin/disease leads t a decrease in bile salt reabsrptin + increase in excretin due t interruptin f circulatin If bile is stpped frm entering the GI tract, up t 50% f indigested fat appears in the faeces, alng with malabsrptin f sluble vitamins A,D,E + K e.g. Crhn s disease The gall bladder Functins Bile strage Bile acidificatin Bile cncentratin reducing the vlume f stred bile by absrbing Na, Cl, Ca + carbnate ins, with a net mvement f water Effects f chlecystectmy Definitin: remval f the gall bladder Bilirubin May be required fr gall bladder cancer r gall stnes Gall bladder is nt essential, as its peridic discharge f bile aids digestin but will require a reductin in fat intake Water insluble yellw pigment Surce: Hb breakdwn in spleen Catablism f haem prteins Ineffective bne marrw erythrpiesis Bilirubin is prduced in spleen then bund t albumin where it dissciates in the liver and enters hepatcytes In the hepatcytes, it binds t cytplasmic prteins and is cnjugated t glucrnic acid t frm diglucrnide-br This is mre sluble than free bilirubin The cnjugated mlecule is then transprted acrss cnc gradient int bile canaliculi and int the GI tract Ttal BR = free uncnjugated BR + cnjugated BR Urbilingens Water-sluble clurless derivative f BR frmed by the actin f GI bacteria n bilirubin GI tract mucsa relatively impermeable t cnjugated BR, but permeable t uncnjugated + urbilingens Therefre sme urbilingens are reabsrbed int the general circulatin, and are excreted via the kidneys int the urine 26

27 The remaining 80% are nt absrbed, therefre are excreted in faeces; first cnverted int stercbilingen which is xidised t give brwn clur f faeces Chlestasis + Jaundice (icterus) Chlestasis = cessatin f bile flw Jaundice = BR >34-50micrM/L in bld (nrmal = 20) Chlestasis nrmally results in jaundice, but jaundice has ther pssible causes Causes Pre-hepatic Prblem is befre the liver, i.e. BR prductin in the spleen is t high May be due t haemlysis, massive transfusin, haematma reansrptin, ineffective erythrpiesis BR prductin is t great fr cnjugatin in the liver, therefre predminantly uncnjugated BR in the bld Lk fr HB drp withut vert bleeding Hepatic/hepatcellular Spleen prductin f BR nrmal, but the hepatcytes f the liver nt functining prperly, either defective uptake, cnjugatin r excretin May cause liver failure (which may be acute, chrnic, caused by viral hep etc) and intrahepatic chlestasis Pst-ehpatic/bstructibe Defect in the transprt f cnjugated BR by the biliary duct system e.g. in the cmmn bile duct Tends t be frm bstructive cause, e.g. gall stnesm liver malignancy, pancreatic cancer, lcal lymphadenpathy Bilirubin stasis increased risk f infectin + sepsis Als leads t upstream dilatatin f bile ducts Treatment: bstructin remval via stent Specific causes Pre-Hepatic Hepatic Pst-Hepatic Inherited disrders f BR metablism: Hepatitis due t: Intrahep chlestasis 2ndary t drugs r virus Crigler-Najjar Viral Primary sclersing chlangitis Gilbert s Autimmune Primary biliary cirrhsis Rtr Drugs Gallstnes in CBD Dubin-Jhnsn Alchl Chlangicarcinma Carcinma head f pancreas Haemlysis Metablic liver disease Carcinma ampulla 27

28 NB: Gilbert s caused by AGT deficiency (plymrphism less effective enzyme in 2% f ppulatin) slightly increased BR which may spike during illness r stress ALSO, ther illnesses cause yellw skin disclratin, e.g. Addisn s, carrtinaemia hwever jaundice als presents with yellw discluratin f the eyes (imprtant diagnstic tl) 28

29 Immunlgical mechanisms & infectins f the alimentary tract Alimentary System 6 - Prf Salim Khak (s.khak@imperial.ac.uk) 1. List the innate functins f the alimentary system which are part f ur defence systems 2. Define MALT + GALT 3. Describe a Peyer s Patch 4. Define the rle f IgA in the GI tract 5. Describe the imprtance f clnic flra 6. Describe the circulatin f lymphcytes within the alimentary system + hw this relates t the immune system elsewhere 7. List 3 mechanisms f infectius diarrhea 8. Describe the glbal imprtance f childhd diarrhea Why mucsal immunlgy? The alimentary system is expsed t many antigens n a daily basis. These antigens can be derived frm fd and frm ptential invaders such as bacteria + viruses. Recgnitin and apprpriate handling f these antigens are vital t survival. If the immune system is prly functining then we are at risk f infectins and if t vigrus can lead t hypersensitivity reactins and aut-immune disease. Examples f GI Pathgens Muth: ral candidiasis Gastric: Helicbacter Pylri In the nrmal stmach, acid secretins maintain a lw ph t aid fd digestin In respnse t H. infectin, gastrin secreted by G cells stimulates excess acid prductin Cntinued excess stmach acid tissue damage + peptic ulcers In sme cases, chrnic inflammatin develps atrphy f the stmach wall + malignant tumurs? Traveller s diarrhea has multiple causes, which include: Escherichia cli (E.cli) Strains + txins: entertxigenic (chlera-like w watery diarrhea) enterhaemrrhagic, enterpathgenic (EPEC), enterinvasive (shigella like w bldy diarrhea + megacln) Rutes f transmissin: farms, unpasteurised milk, burgers Treatment: usually supprtive, but sever cases antibitics are used Nravirus faec-ral transmissin with 24-48hr incubatin perid acute gastrenteritis <3 days, but may be infectius fr up t 2 weeks Chlera gram negative extracellular bacillus targets Cl- channels huge water + salt lss in ricewater like diarrhea. Causes extreme dehydratin + pssible hypvlaemic shck Treatment: supprtive (fluid replacement, salt, water, sugar + IV fluids) Als shigella, salmnella, rtavirus, giardia superbugs f the 21 st C - Clstridium difficile (C. Diff) The cln is clnized by large numbers f cmmensal gut bacteria + Antibitics kill many f these C. Diff gains a fthld + prduces txins mucsal injury Neutrphils + RBC leak int gut between injured epithelial cells Causes pseudmembranus clitis (antibitic assciated), bldy diarrhea, mucus + abdminal pain Treatment: islatin, stp current antibitics, metrnidazle + vancmycin NB: Fd intlerance may als cause symptms f GI disease e.g. diarrhea Nuts, Hen egg white, Cw s milk, Wheat, sesame seeds, sya + shell fish 29

30 GI Immunlgy Innate GI Defence Gastric acid Cmmensal ral flra Peristalsis Mucus secretin frm gblet cells Prteases intraluminal enzymes Prtective shield f the entercyte membrane + brush brder Gut immunity We are expsed t thusands f antigens n a daily basis. There are tw immunlgical defences f the GI tract, clsely related t the prminent lymphatic supply/draining f the gut: MALT mucsa assciated lymphid tissue The ral cavity is rich in MALT, e.g. the tngue, palatine, lingual + pharyngeal tnsils GALT gut assciated lymphid tissue May be rganised r nt rganised Nt rganised GALT cnsists f intra-epithelial lymphcytes (mainly CD8) + lamina prpria lymphcytes (antigen presenting cells) Organised GALT cnsists f cryptpatches (tiny lymphid aggregates present in the small intestine), Peyer s patches (in the distal ileum), islated lymphid fllicles + mesenteric lymph ndes Functin: generated lymphid cells + antibdies: IgA, IgG, IgM + induced cell mediated immunity Within the Gut mucsa, there are regins f epithelium which are specialised t frm dme epithelium These are areas f M cells instead f mucsal epithelium ; effectively areas which cntrl the uptake f antigens Frmed by smaller epithelial cells with less gblet cells, less mucus + n secretry IgA M cells frm the prtal f entry fr antigens, where they are transprted t lymphcytes, macrphages + dendritic cells IgA the specialised immunglbulin f the gut transprted frm submucsa t lumen by transcytsis Dimeric IgA secreted by plasma cells in the submucsa, which then binds t the ply-ig receptr n the eptiehlial cell membrane Receptr + IgA endcytsed t frm vesicle, then underg enzymatic cleavage t frm secretry IgA which is secreted int the lumen M cells present in dme epithelium Unique ability t transcytse antigens, presenting them t plasma cells within rganised lymphid fllicles f the submucsa Alternatively, can present the antigens t a pl f cytkines + lymphcytes (predminantly T cells) in a pcket n their baslateral side The pl f cytkines is knwn as a cytkine milieu + affects develpment f the uncnventinal resident T cells f the gut The plastic respnse f T-cells t this milieu can lead t a prinflammatry envirnment, leading t an increase in Th1, Th IL 17 with a decreased Treg cell cunt Intraepithelial lymphcytes make up 20% f the intestinal epithelium, and cnsist f 2 different grups f T cells Cnventinal T cells; migrated frm ther tissues Uncnventinal T cells; resident T cells which express unusual cmbinatins f CD4, CD8 r γδ TCR Grups f CD4 cells: Th1 cellular immunity + autimmunity Th2 humral immunity, atpy, asthma + allergy 30

31 Treg immunregulatry functin Th IL 17 inflammatin + autimmunity Adaptive immune respnse M cells transprt antigens int submucsal rganised lymphid tissue, present t plasma cells, which secrete IgA Innate immune respnse Infectin f an epithelial cell signals the synthesis f a series f stress-induced prteins, expressing 2 atypical MHC class I mlecules knwn as MIC-A +MIC-B T cells bearing the NK receptr NKG2D binds t the atypical mlecules Infected cell is then killed by inductin f apptsis + replaced by adjacent healthy cells Clinical Crrelates Celiac disease Subttal villus atrphy with gluten intlerance Pathgenesis: dendritic cells f the submucsa mature in a prinflammatry envirnment f increased Th1 + Th IL 17, with reduced Treg cunt Crhn s disease The gut has a dual immunlgical rle: immunreactivity + fd tlerance (acquired tlerance t fd antigens suppressin f humral respnse) Crhn s is an acquired tlerance failure, in which individuals d nt suppress humral respnse t fd, therefre becme hypersensitive t the fd antigen Symptms include structuring, ulceratin + inflammatin Related t an increased TGF-beta caused by either cytkine secretin f IL-10 (assciated with a lw dse expsure) r anergy deletin (assciated with a high dse expsure) Primary sclersing chlangitis Inflammatry cnditin f the biliary tree assciated with inflammatry bwel disease May cause chlangicarcinma Cause is T-cell misdirectin t the liver whether they cntribute t inflammatin + biliary destructin 31

32 Organisatin f the Liver Alimentary System 7 Dr Jeremy Cbbld (j.cbbld@imperial.ac.uk) 1. List the main functins f the liver 2. Review the rganisatin f the liver + biliary system at the level f grss anatmy 3. Describe the main features f the bld supply t the liver 4. Explain the rganisatin f liver tissue in relatin t its micrcirculatin, making crrect used f the terms prtal triad, central vein, sinusidal capillary, hepatcyte, lbule, periprtal regin + centrilbular regin 5. Summarise the functinal imprtance f main structural features f hepatcytes (RER, glgi, secretin granules, glycgen granules, mitchndria, smth ER, junctinal cmplexes) 6. Draw a simple diagram utlining the relatinships f hepatcytes t bile canaliculi + sinusidal capillaries, and use this t explain majr hepatic functins 7. Define the psitin + main rles f Kupffer cells (fixed macrphages) 8. Outline the embrylgical rigins f the liver 9. Explain the main structural + functinal changes in the liver between the embrynic perid + pstnatal perid Summary f lecture structure: surface anatmy, mrphlgical anatmy, bld supply, functinal anatmy, biliary system, embrylgy, histlgical structure + ultrastructure Surface anatmy The abdminal regin can be divided int 4 quadrants The liver is a large slid rgan which sits in the right upper quadrant (predminantly, als in left UQ) The superir brder tends t lie at the level f the 5 th cstal cartilage Prtected mainly by ribcage, superirly by the diaphragm + inferirly by the abdminal muscles + rgans Imprtance f surface anatmy The liver is a very friable rgan, and any damage t the liver is very painful and may cause severe bleeding (capsule surrunding liver is very well innervated, and the liver itself is very vascular) Surface anatmy is used in liver bipsy, as knwledge f the lcatin f the liver prevents damaging ther rgans Percussin f chest inferirly, and percussin f abdmen superirly when dull regin is reached = liver Large inspiratin fllwed by expiratin prir t insertin f needle Bipsy used t determine diagnsis + staging f liver disease Mrphlgical anatmy The liver cnsists f 2 lbes, separated by the falcifrm ligament The crnary ligament + left triangular ligament cnnect the liver t the abdminal wall + diaphragm The gall bladder lies inferirly in the arch f the liver, therefre shuld nt be palpable if the gall bladder is palpable; indicates enlargement 32

33 Bld supply The liver is a very vascular rgan, due t its imprtance in metablism + hmestasis thus receives 25% f the resting cardiac utput Has a dual bld supply: arterial and venus 20% artery bld frm L + R brances f the hepatic artery xygen rich 80% venus bld draining frm the gut thrugh the hepatic prtal vein nutrient rich This prvides the liver with bth a direct + indirect bld supply, which reduces the risk f acute ischemia if emblus present NB: hepatic lesins will receive arterial supply mre rapidly than the venus supply, therefre cntrast medium can be used in liver imaging t bserve the effect n the arterial supply Functinal anatmy The mrphlgical lbes f the liver crrespnd t the attachement f the mesenteries and the lcatin f the falcifrm ligament Hwever functinally, the liver is divided between the territries f the R + L branches f the hepatic artery Centrally, the liver is divided by the hepatic prtal vein, hepatic artery + bile duct Peripherally, the liver is then divided int 8 functinally independent segments, all with their wn hepatic vein branch, which calesce int the R + L hepatic veins which drain int the IVC This means that each segment can be resected withut bleeding + damaging the surrunding segments this is knwn as a bldless liver surgery, and is cmmn fr surgical tumur remval The segments are numbered clckwise frm the psterir central caudate lbe, and this is imprtant in radilgy fr lcating hepatcellular carcinmas n CT scans Functins f the liver Secretes bile int dudenum + synthesis f bile salts Phagcytses + breaks dwn ver-dates RBC Excretes bile pigments int bile Metablises many natural + synthetic mlecules t prepare them fr excretin Synthesis + secretin f key bld prteins Key site f insulin dependent glycgen strage + f intermediary metablism Many thers Digestin Liver has a key rle in Energy Metablism Bisynthesis Degradatin Detxificatin Embrylgical rigins The liver + biliary system share a cmmn rigin with the ventral part f the pancreas at the junctin between the fregut + midgut Arises frm the septum transversum pint at which the ectderm f the amnin meets the endderm f the ylk sac The mesenchymal structure f the septum prvides a framewrk n which the parenchymal (hepatcyte) cells + bile ducts with assciated bld supply can develp 33

34 The biliary tract The biliary system as an imprtant rle in the excretin f txins + secretin f fats Hepatcytes within the liver prduce bile, and secrete this int bile canaliculi which drain int ductules ducts and eventually drain int the hepatic duct The gall bladder serves as a reservir f bile between meals, and has a cystic duct which fuses jins the gall bladder t the hepatic duct t frm the cmmn bile duct The cmmn bile duct has a spiral muscular structure which twists/untwists; n untwisting f the duct + sphincter f Oddi, it becmes patent + secreted bile int the ampulla in the 2 nd part f the dudenum At the ampulla, the CBD may als jin the pancreatic duct Bile neutralises chime + aids digestin f fats, therefre structural abnrmalities f the biliary tree may have devastating effects n digestin The biliary tree can be seen using ERCP (endscpic retrgrade chligraphic pancreatgraphy A wire is passed thrugh the spinchter f Oddi (alng with a scpe), and dye is injected t the see the branches f the bile ducts This can be used t see any bstructins, e.g. gall stnes r tumurs Is als gd because as it is invasive, prvides pprtunity t slve prblem fund, e.g. remving the bstructin MRI can als be used t bserve the effects f gall stnes r tumurs n the biliary tree, e.g. dilatin due t accumulatin f bile, r cnstrictin f the distal end f the bile duct Histlgical structure The liver cnsists f unit knwn as lbules These cnsist f a central vein (which drains int hepatic veins IVC) with radiating hepatcyte sheets Raund the edges f adjining lbules are prtal triads cnsisting f: Hepatic arterile Branch f the hepatic prtal vein Bile duct Between the sheets f hepatcytes + capillary sinusids which eventually drain int the central vein There are als bile canaliculi which drain the bile prduced in the hepatcytes int ductules which flw utwards int the prtal triad Cell types Hepatcytes are the main functinal cells, bile prducing, make up apprx. 80% f liver cells Endthelial cells line all the bld vessels and sinusids f the liver Chlangicytes lining the biliary tree + branches, including bile canaliculi Kupffer cells are liver resident macrphages (larger, darker mre flattened nuclei cmpared t hepatcytes) these breakdwn RBC + chregraph immune respnses in the liver Hepatic stellate cells are Vit A strage which may be activated (by txic insult, immune invasin, reactive xygen etc) t frm fibrgenic myfibrblastic phentype depsitin f fibrus tissue causing liver fibrsis and eventually cirrhsis Lbule vs acinus (see previus liver ntes fr mre detail) Lbules are the histlgical units within the liver which are easily identified and are centred arund central veins which drain int the hepatic veins Acini are functinal units which are aligned arund the prtal triad, and divided int znes dependent n their prximity t arterial bld supply These are less easy t visualise, but pattern f cell death related t acini znes which can be seen in micrscpy 34

35 Ultrastructure Shwn n EM The space between hepatcytes + their assciated sinusid endthelium = Space f Disse The endthelium is fenestrated t allw the mvement f substances, and Kupffer cells reside in the space In a nrmal liver, the hepatcytes are healthy, cvered in micrvilli. The space f Disse is clear, with kupffer cells + stellate cells, and the endthelium f the sinusids are fenestrated In liver disease, they hepatcytes lse their micrvilli, endthelium lse fenestrae, the stellate cells depsite fibrus tissue int the space f Disse. There is als an upregulatin f Kupffer cells which leads t the prductin f free radicals which cause further damage There are different stages f fibrsis: mild-mderate, mderate bridging and full cirrhsis Fibrus tissue affects the bld supply t healthy hepatcytes energy supply/detxificatin functin lss Cirrhsis ccurs when there is decmpsitin f surrunding liver tissue failure, immunsuppressin, hypertensin (at lcatin f prtsystemic anastmses), vmiting f bld A B 35

36 Pancreatitis Alimentary System 8 Prf Gerge Hanna (g.hanna@imperial.ac.uk) 1. Define acute and chrnic pancreatitis 2. List fur causes f acute pancreatitis 3. List the symptms and signs f acute pancreatitis 4. List bld tests and imaging mdalities which are useful fr patients with pancreatitis 5. List three causes f chrnic pancreatitis 6. List the cmplicatins f acute and chrnic pancreatitis Intrductin Inlammatry disease f the pancreas has tw different entities acute and chrnic. The pancreas is a lng flat gland that lies hrizntally behind the stmach. The head f the pancreas rests against the dudenum and the tail reaches twards the spleen. It has tw main functins: 1) Excrine: Prductin f digestive juices and enzymes fr the metablism f fats, carbhydrates and prtein. 2) Endcrine: Secretin f insulin, glucagn and smatstatin. The pancreatitis has an incidence f 17 new cases per 100,000 peple. Acute pancreatitis Is an acute inflammatry prcess f the pancreas with variable invlvement f ther reginal tissues r remte rgan systems. Clinical presentatins: 1.Severe acute pancreatits, 2. Mild acute pancreatitis, 3. Acute fluid cllectin, 4. Pancreatic necrsis and infected necrsis, 5. Acute pseudcyst, 6. Pancreatic abscess. Mrtality has remained at 10-15% ver the past 20 years. Causes: The mst cmmn causes f pancreatitis are alchlism and chlelithiasis. Other causes are metablic, infectins, medicatins and vasculitis. Clinical diagnsis: Histry f upper abdminal pain and vmiting with epigastric r diffuse abdminal tenderness. Occasinally bdy wall ecchymsis (Cullen`s sign at the umbilicus, Grey-Turner`s sign in the flanks) will be fund. Bichemical diagnsis: Elevated levels f pancreatic enzymes, amylase and lipase. Elevated white bld cell cunt, liver enzymes and bilirubin, hyperglycemia, hypcalcemia. C-reactive prtein (CRP) cncentratin has independent prgnstic value. A peak level f > 210 mg/l in the first fur days f the attack r > 120mg/l at the end f the first week has a predictive accuracy f arund 80%. Radilgical diagnsis: Plan x rays: Chest and abdminal plain x rays in rder t detect lcal ileus (sentinel lp) and in case f the chest x ray the pleural effusin is the mst cmmn finding and the alvelar interstitial shadwing may suggest an adult respiratry distress syndrme (ARDS). Ultrasund: Is valuable in detecting free peritneal fluid, gallstnes, and dilatatin f the bile duct. MRCP: Nn-invasive investigatin f the bile duct. ERCP: In patients thught t have a severe biliary pancreatitis secndary t gallstnes. CT-scanning: Fr the diagnsis and eventually fr the drainage f fluid under radilgical guidance. Severity stratificatin: Bichemical and bjective criteria: Glasgw and Ramsn scring systems. Thse scring systems imprve the accuracy f prgnsticatin arund 70-80%. The APACHE II scring system can be used t assess the initial severity f disease and the chances f develping a subsequent cmplicatin. Management f mild acute pancreatitis: Mnitring f temperature, pulse, bld pressure, and urine utput. Line fr IV fluids, nasgastric tube and urine catheter. Antibitics shuld nt be administrated rutinely as there is nt evidence that their use in mild cases will affect utcme r reduce the incidence f septic cmplicatins. Nutritinal recmmendatins: 2-5 days: fasting, 3-7 days: referring (diet rich in carbhydrates, mderate prtein, mderate in fat). After 7 days may start a nrmal diet. Management f severe acute pancreatitis: The initial management invlves full resuscitatin and a multidisciplinary apprach. These patients shuld be managed in ITU. When cardicirculatry cmprmise exists a Swan-Ganz catheter is required. The administratin f intravenus antibitics as a treatment f infectins 36

37 fllwing severe acute pancreatitis is justified. CT scanning shuld be dne. Nutritinal supprt: enteral/parenteral. Enteral nutritin shuld be attempted in all patients. The severe gallstne pancreatitis shuld be treated with ERCP and sphinctertmy urgently. Gallstnes eradicatin shuld be dne by chlecystectmy within tw r fur weeks. If lcal cmplicatins develp, such as pseudcyst r infected necrsis, chlecystectmy shuld be perfrmed when the cmplicatins are treated surgically. Chrnic pancreatitis The mst cmmn causes f chrnic pancreatitis are alchlism, micrlithisasis and idipathic. Rare causes are hereditary pancreatitis, hyperparathyridism, and bstructin f the main pancreatic duct caused by stensis, stnes r cancer. Symptms may be identical t thse f acute pancreatitis. Althugh ccasinally there is n pain, severe epigastric pain may last fr many hurs r several days. Pssible causes include acute inflammatin nt recgnised by cnventinal tests, distensin f pancreatic ducts caused by strictures r calculi, a pseudcyst, r bstructin f either the dudenum r the cmmn bile duct caused by fibrsis f the head f the pancreas. When lipase and prtease secretins are reduced t < 10% f nrmal level, the patient will develp steatrrhea. Diagnsis: Labratry tests, including amylase and lipase, are frequently nrmal, prbably because f significant lss f pancreas functin. Inflammatry markers can be minimally elevated as well. Structural abnrmalities can be visualised in plan x-ray abdmen, shwing pancreatic calcificatins, which indicates intraductal stnes. Abdminal ultrasund, CT scan can shw abnrmalities in size and cnsistency f the pancreas, pancreatic pseudcysts, r dilated pancreatic duct. The ERCP can shw abnrmalities in the pancreatic duct. Tests t assess the endcrine functin f the pancreas can shw diabetes mellitus. The mst sensitive tests f the excrine functin f the pancreas: is the secretin test. Other tests include measurement f serum trypsingen, faecal chymtrypsin, and urinary p-aminbenzic acid. Treatment: A relapse f chrnic pancreatitis may require similar management t that f acute pancreatitis. The supply f IV fluids, dietary restrictin including fat and prteins in rder t reduce stimulus t the pancreas secretin. H2 r PPI blckers t reduce acid stimulatin and relieve f the pain. T treat the chrnic pain, pancreatic enzymes (30,000 U f lipase) have been used with each meal. A pancreatic pseudcyst can be decmpressed int a nearby structure eg. stmach r int a defuntinalized lp f jejunum via a Rux-en-Y. If the pain is refractry and the main pancreatic duct is dilated a lateral pancreaticjejunstmy (Puestw Prcedure) may be indicated. If the duct is nt dilated a resectin can be cnsidered like a distal pancreatectmy r Whipple`s peratin. These perative appraches may relieve pain in 60 t 80% f patients and shuld be reserved fr patient with a nndilated duct wh have discntinued using alchl and wh can manage diabetes that may be intensified by pancreatic resectin. Steatrrhea can be imprved with pancreas extracts cntaining lipase. H2 blckers can be used t reduce the intragastric acidity. Use f Insulin t treat the diabetes shuld be managed carefully due t the assciated glucagn deficiency. Patients with chrnic pancreatitis are at increased risk fr pancreatic cancer. Wrsening f symptms shuld prmpt an examinatin fr malignancy, including brushing f strictures fr cytlgical analysis r measurements f serum markers (eg. CA 19-9, CEA). EXTRA NOTES Pancreas is retrperitneal. If enzymes are released in active frm, self-digestin can ccur Excrine functin: ducts, released at particular times. Endcrine functin: insulin + glucagn, int bldstream Lcatin f pancreas: sits under liver behind stmach abve transverse cln. Lies at trans-pylric plane. Dudenum encircles head + neck f pancreas. Imprtant: if pancreas is inflamed, it affects the dudenum + halts peristalsis. Makes patient nauseus + vmit. Main symptm f pancreatitis: pain (inflammatin + visceral spread via celiac plexus). Inflammatin can lead t chlestasis + jaundice, + aut-digesting enzymes can affect bld vessels + lead t bleeding. Pancreas: yellw, shiny rgan. Parts f pancreas: see previus lecture. Back f pancreas: main pancreatic duct jins bile duct 37

38 Bld supply: gland develps between fregut + midgut. It therefre gets bld supply frm mre than ne artery Clinical imprtance: hypertphy f head causes bstructin. Degeneratin f islets f Langerhans leads t DM. Pancreatitis is an inflammatry cnditin f the excrine pancreas. Cancer f the head is ften fatal (pr prgnsis). Micrscpic anatmy: islets f langerhans PANCREATITIS: definitin, epidemilgy, causes, pathphysilgy, diagnstics, prgnstic markers, management, cmplicatins. Definitin: itis i.e. inflammatin. Acute vs. chrnic. Particular triggers. Acute pancreatitis is activatin f all prcesses befre digestive hrmnes have been released. Enzymes are nrmally released in precursr frm. Substances within gut then activate these precursrs, therefre preventing damage t structure f pancreas. Hwever in pancreatitis, the pancreas is activated when yu pass gall stnes/drink t much alchl etc. Incidence: 3% f cases f abd pain. Lwer prevalence in Japan (less alchl). Can ccur at any age, but majr peaks are yung males (alchl) and lder females (gall stnes). N gegraphical predispsitin but in reality a disease f the Western wrld. Mst cmmn causes: Get smashed gall stnes, ethanl, trauma, sterids, mumps, autimmune, scrpin bites, hypthermia/vlaemia, OR hypertriglyceridaemia/calcaemia, ERCP (prcedure), drugs (e.g. estrgen, tetracycline, thiazide, metrnidazle, simvastatin, sulfnamides) Pathlgy: micrscpic (inflammatin + autdigestin/autlysis + leakage), macrscpic (sapnificatin, haemrrhage, fat necrsis, infectin) Symptms: RUQ/epigastic pain, vmiting, dehydrated/shck, jaundice (bstructive), indicatins f causes (alchl, disease e.g. mumps) Signs: ften lk quite well, cnfused. 3 respnses t trauma: bdy s healing prcess is verwhelming, bdy s healing prcess is underwhelming, bdy has a balanced healing prcess. Mst unwell peple tend t be the elderly, highly febrile, tachypnea, tachycardia, shck, abdminal distensin, tender/guarding/rebund, Grey- Turner s (haemrrhagic), Cullen s (bruising arund umbilicus as bld tracks dwn falcifrm ligament), ascites, epigastric mass, tetany (transient hypcalcaemia), ARDS Tests/investigatins: assessment, full histry + examinatin, urine, blds (FBC, U&Es, LFTs, lipase, LDH, calcium, CRP), ABGs. Raised amylase: caused by many different disrders, s must fit with a histry f pancreatitis. Other tests: CXR (t rule ut acute abdmen free air under diaphragm), ECG, AXR (gallstnes, calcified pancreas, sentinal lp), USS (rules ut gallstnes), CT Other imaging mdalities: EUS, ERCP, MRCP Prgnstic indicatrs Ransn s/glasgw Criterir, APACHE Treatment: resuscitate, cnfirm diagnsis, admit, IV access, catheter, NGM/NGT, analgesia, DVT prphylaxis, central line, manage alchl related prblemts, antibitics, PPI, address feeding prblems, treat the cause, treat cmplicatins, be prepared fr prblems (medical, surgical, scial) Cmplicatins: lcal, general, early, late Lcal: necrsis, abscess, haemrrhage, pseudcyst/ther fluid cllectins, excrine/endcrine dysfunctin, pancreatic fistulae, psedaneurysm, pancreatic ascites, chrnic pain General: MODS, ARDS, renal failure, cma, liver failure, cagulpathy 38

39 Malnutritin II Obesity Alimentary System 9 - Stephen Rbinsn (Stephen.rbinsn@imperial.ac.uk) 1. Describe the principles f energy balance 2. Describe methds f assessment f energy stres + risks 3. Understand mechanisms f besity 4. Describe cmplicatins f besity 5. Understand the basics f besity management Energy Balance Maintaining weight reflects an energy balance balance between energy intake + expenditure Obesity reflects a psitive energy balance, caused by an increased intake. Hwever besity leads t anincreased ttal energy expenditure. Energy intake cnsists f prtein, fat and carbhydrate Mst f ur energy expenditure = resting energy expenditure (i.e. BMR) but physical activity + thermgenesis als imprtant Any increase in energy intake tends t be stred as fat (initially tipping the energy balance). Hwever a new balance is then set at a higher value (reasn that an bese individual will require mre calries t maintain weight) E.g. a 70kg weight = 56kg fat-free mass with 14kg fat mass. A 80kg weight will have 60kg f fat-free mass, with 20kg fat mass the energy balance is then re-set t maintain this The ideal intake f energy is ½ cmplex carbs, fllwed by fat + prtein. Hwever the typical western diet has a higher fat intake. Energy expenditure majrity is resting energy expenditure, cming frm maintaining temperature, in cncentratin AND string prtein + carb (strage f prtein + carb requires energy!) Assessment f energy stres + risks Definitin f besity is in terms f weight/height 2 = BMI 25-30kg/m 2 = verweight >30kg/m 2 = bese Hwever reginal adipsity/energy partitining is a better assessment fr disease risk, mrbidity + mrtality NB: there is an increasing trend in besity in bth the UK + US Obesity can be cnsidered a metablic syndrme cnsisting f a cnstellatin f risk factrs which happen t cseggregate: Waist circumference (men>102, wmen>88) if mental fat > peripheral fat, there is a greater assciated risk fr CVD (especially CHD) T2DM (its mre than besity increased risk) assciated with micralbumin + insulin resistance Hypertensin (bp>135/80mmhg) HDL cunt (men<1.0, wmen<1.3) Fasting glucse (>6.0mml) Mechanisms f besity Obesity can be seen as a multifactrial disease, with influences frm genes, envirnment + sciety Causes t cnsider include energy intake/energy usage, genetics, brain/endcrinlgy, behaviur/culture Energy intake vs. energy usage 39

40 Genes The intake f energy in the general ppulatin has been relatively cnstant, hwever there has been a change in dietary patterns f energy cnsumptin (increased fat, decreased carbhydrate) this has an imprtant effect n energy strage + satiety (carbs make yu feel full) Diet cmpsitin is imprtant t weight gain as fat is the main strage fuel + autregulatin fllwing fat is imprtant There is als an assciated with increased fat/decreased carb reduced satiety (althugh cntrl f stiety has cmplex endcrinlgy) It is difficult t measure quantity f energy expenditure, but technlgical advances has led t a big reductin in verall energy expenditure it is prven that maintaining a high physical activity reduces risk f besity in bth men + wmen Mst besity is nt mngenic, but the amunt and site f weight gain is part genetic (shwn by study f weight gain in twins) The study f T2DM has led t the identificatin f a cmmn variant in the FTO gene which is crrelated t a 3kg weight increase in the 16% ppulatin wh has hmzygus Genes may als influence preference fr type f fd, i.e. whether yu chse junk r fruit Brain + endcrinlgy White adipse tissue makes a hrmne called leptin, which signals t the hypthalamus that the bdy has sufficient energy stres + satiety Rare leptin deficieny besity as n satiety drive Hwever mst bese individuals have an increased leptin, due t increased white adipse tissue Leptin is actually mre imprtant in underweight individuals signals need fr fd by chregraphing additinal bdy respnses t reduced fat, e.g. stpping menstruatin + reduced antibdy cunt NB: insulin als has a rle in satiety cntrl Other hrmnes include grehlin (frm stmach) + PYY (frm intestine) which are imprtant in the cntrl f satiety + hunger respectively. Leptin, grehlin + PYY are imprtant targets fr treatment f besity, but are less imprtant when cnsidering the cause Behaviur + culture Individual behaviur + scietal changes have cntributed t besity, e.g. driving t wrk instead f wrking Cst f healthy fd als influences, therefre link between besity + sci-ecnmic class suggested Cmplicatins f besity Obesity increases mrbidity + mrtality risks in bth men + wmen There are als ecnmic + psychlgical csts assciated with besity Obesity als has an assciated increased risk fr many diseases, including cardivascular, GI disease, chest disease, endcrine, gynaeclgical + bstetric With an increased BMI, there is increased mrtality with reduced life expectancy in bth men + wmen, e.g. BMI f 35 as ppsed t 30 reductin f life expectancy f 1 ¼ years Obesity management First, we need t establish the reasn fr besity management this shuld nt be a persnal pinin, but rather fllwing EBM n assciated mrbidity + mrtality Firstly lifestyle, diet + exercise shuld be cnsidered pharmaclgical interventins + surgery shuld be a later resrt 40

41 Benefits f mderate weight lss include psychlgical benefits, imprvement f plycystic varian syndrme, esphagitis, CHD, angina, stearthritis, liver functin, pregnancy + diabetes There is als an assciated reductin in mrtality, bld pressure, risk f T2DM, LDL cunt + increase in HDL cunt Diets the atkins diet is assciated with the greatest weight lss ver 12 mnths. Hwever EBM shws that diets are suited t individuals Hwever all supprt physical activity in cnjunctin with diet Prblem with bese patients is that the difference between ideal + actual utcme f weight lss leads t a psychlgical barrier making cnventinal weight management (including diet + activity changes) fail ver the lng term Fr lng term treatment, pharmaclgical interventin as supplementatin f lifestyle changes mre successful hwever there is nly ne current licensed drug = rlistat; a GI lipase inhibitr which reduces fat absrptin (ther drugs have been taken ff market due t adverse effects) surgery has nw becme a viable ptin fr bese patients; including gastric bypass + gastric banding gastric bypass prevents calries cming int cntact with the dudenum, which reduces calrie absrptin gastric banding reduces the size f the stmach, prmting earlier satiety surgery may becme a mre cmmn treatment in the future 41

42 Liver failure Alimentary System 10 Dr Belinda Smith Summary f Functins f the Liver Excretin f Bilirubin Chlesterl Hrmnes Drugs Enzyme Activatin Strage f Glycgen Regulatin f glucse cncentratin Vitamins Synthesis f Plasma prteins such as albumin and cltting factrs Bile Detxificatin Immune Regulatins Kuppfer cells release antigens frm the gut and remve immune cmplexes frm the bld NB: the wide variety f the functins f the liver are facilitated by the rich dual bld supply the liver receives (systemic + hepatic prtal vein), and due t the clse prximity f the highly permeable sinusidal capillaries and functining hepatcytes. Liver Failure Definitin = insufficient hepatcyte functin t maintain nrmal hmestasis Liver Failure can be characterised by Rate f Onset the rate f decline f functin determines the way in which the syndrme manifests + the likely utcme Cause Clinical Features the main clinical features are a cnsequence f the accumulatin f txins resulting frm the lss f the detxifying functin f the liver Pathphysilgy Histlgically, the liver can be divided int plyhedrns f hepatcytes called lbules. Sinusidal capillaries drain the hepatcytes int the middle central vein (branch f hepatic vein), and there are peripheral prtal triads (branch f the hepatic artery, prtal vein + bile duct) Liver failure can thus be seen as centrilbular necrsis f hepatcytes it has n cnstant hepatic pathlgy but rather it is a functinal syndrme May be assciated with: Mnnuclear cell infiltrate e.g. mncytes + macrphages, which affect the prtal tract and lbules Fatty change seen depending n the aetilgy Activatin f macrphages Release f cytkines such as TNF. IL-1 and IL-6 (prinflammatry) Aetilgy The cause f the liver failure dictates the rate f nset, clinical presentatin and eventual utcme Acute liver failure - This develps within 6 mnths in a previusly nrmal liver and is further divided int three grups accrding t the rate f nset, the interval between the nset f jaundice and encephalpathy; hyperacute, acute and subacute 42

43 Chrnic liver failure - failure may develp due t the gradual prgressin f a pre-existing underlying liver disease r may be precipitated by an additinal new insult in a patient with a previusly cmpensated liver disease Amanita phallides (Death Cap) They taste pleasant They have a fatal dse f 30g Risk is nt decreased by cking It has delayed presentatin Liver and kidney failure N antidte Clinical features + pssible cmplicatins General ill-health and fatigue Jaundice Hyperdynamic circulatin Fever and sepsis Muscle wasting Skin and endcrine changes Hepatic encephalpathy (acute) This ccurs with bth acute and chrnic liver failures Reversible neurpsychiatric state due t the brain being expsed t increased levels f ammnia and ther neurtransmitters. Impairs cngitin + cnsciusness Caused by hepatcellular dysfunctin + hepatcellular dysfunctin Has 4 grades: 1= cnfused, 2=drwsy, 3=sleeping but ruseable, 4= cma, unruseable Cerebral edema (acute) Disruptin f bld brain barrier and increased smsis int brain. Caused by increased cartid artery pressure (> intracerebral pressure increased ICP) Cause f death in 30-50% f acute liver failure May cause death by brain stem herniatin r cerebral hypxia Clinical features include systlic hypertensin, increased muscle tne, myclnus, decerbrate psturing, dynscnjugate eye mvements, lss f pupillary reflexes, respiratry arrest Ascites (chrnic) This is anther cmmn feature f chrnic liver failure Extracellular fluid within the peritneal cavity Due t perceived reduced circulatin plasma vlume sdium retentin, pstural hypertensin + hypalbuminaemia Cmplicatins include spntaneus bacterial peritnitis, renal failure + encephalpathy Cagulpathy (acute) Failure causes synthesis f cagulatin inhibitrs + prteins invlved in fibrinlytic cmplex increase fibrinlysis (breakdwn f clt) Platelet cunt falls and platelets dysfunctinal Bleeding f mucus membranes, GIT and brian Metablic Effects (Acute) Decrease in glucse (hypglycaemia) due t high insulin and decreased liver uptake and glucnegenesis. Decrease in ptassium due t increased urinary lss Decrease in sdium Metablic acidsis 43

44 Infectin (acute) Cmmn in bth acute + chrnic liver failure Pr hst defences due t kuppfer cells + plymrphnuclear dysfunctin Increased access fr infectin biprduct f endtracheal tubes, lines etc Bacterial infectin includings gram psitive e.g. staph Fungal infectins cmmn, but ften unrecgnized (pyrexia unrespnsive t antibitic) Renal Failure Acute Tubular Necrsis Caused by acute liver failure Hepatrenal Syndrme A feature f chrnic liver failure and refers t a functinal renal failure Can be caused by Renal vascnstrictin Decreased renal release f prstaglandins Sepsis Bleeding and hyptensin Prtal Hypertensin(chrnic) The Prtal Venus System It carries bld frm the abdminal alimentary tract, including the spleen, gallbladder, pancreas and bwel, t the liver The nrmal prtal pressure is 7mmHg Prtal Hypertensin r Blck This is equivalent t liver ndule develpment Cllaterals develp Prtal-systemic shunting als ccurs leading t Encephalpathy Septicaemia Impaired liver regeneratin Oesphageal Varices The lwer esphagus is supplied by the left gastric vein but culd drain int the azygus system The deviatin f bld leads t caricsities in the lwer end f the esphagus Bleeding will lead t haematemesis (vmiting f bld), melena (black, haemrrhagic faeces) r encephalpathy This can be treated by the Sengstaken Blakemre tube Acute Liver failure Can be further subdivided int: Hyperacute refers t less than 7 days between jaundice and encephalpathy Acute refers t an interval f 1 t 4 weeks between jaundice and encephalpathy Subacute refers t an interval f 5 t 28 weeks between jaundice and encephalpathy This usually has specific aetilgies prviding the cause f the liver failure Hyperacute = paracetaml, Hep A + B Acute = Hep A, B +E, Idisyncratic drug txicity Subacute = Nn A nn B hepatitis Underlying Physilgy The principle clinical manifestatins results frm disturbances in the hepatic functins, relating t Cagulatin Salt and water hmestasis Vasdilatatin Remval f txins Infectin cntrl 44

45 Causes Nitrgen and glucse metablism Prtal pressure Bilirubin metablism Infectin Viral hepatitis is the mst imprtant cause fr acute liver failure wrldwide Hepatitis A and B cause hyperacute and acute liver failures Hepatitis E can cause acute liver failure NANB (Nn-A, Nn-B) Hepatitis can cause subacute liver failure Herpes Simplex Virus Epstein-Barr Virus Varicella virus Amanita phallides is a death cap tadstl fungus Drugs Paracetaml verdse is the mst cmmn cause and respnsible fr 70% f acute liver failure cases in the UK Paracetaml causes hyperacute liver failure Idsyncratic drug txicity wuld cause acute liver failure Isniazid Ecstasy Halthane Metablic Wilsn s Disease Reye s Syndrme Cardivascular Budd-Chiari Syndrme Ischaemic heart disease Miscellaneus Fatty liver f pregnancy Lymphma Idipathic Clinical features Hepatic encephalpathy Cerebral edema Cagulpathy Metablic infectin Rare causes Budd-Chiari Syndrme Obstructin f hepatic veins at any site frm lbule t right atrium Presents with abdminal pain, hepatmegaly, ascites Histlgy shws sinusidal distentin Causes include thrmbphilia, ven-cclusive disease Wilsns Disease Autsmal recessive disease Cpper accumulatin in the liver, basal ganglia + crnea Caused by failure f cpper excretin in bile Can present with acute r chrnic liver disease 45

46 Treatment is simple = penicillamine = cpper chelatr Symptms include CNS effects, renal bne + haemlytic effects + Kayser Fleischer rings surrunding crnea (usually accmpanying neur prblems, but may be absent in acute presentatin) Acute fatty liver f pregnancy Inherited defects f fatty acid xidatin Incidence 1:1000 UK Presents in 3 rd trimester with RUQ pain, vmiting unrelated t mrning sickness Later leads t jaundice, encephalpathy, ascites, bleeding Treatment urgent delivery with supprtive care Chrnic Liver Failure Causes It develps in a patient with existing advanced liver disease thus the causes reflect the cmmn causes f cirrhsis f the sciety: Alchlic Liver Disease Chrnic Viral Hepatitis B and C Autimmune and Chlestatic Liver Disease Primary Biliary Cirrhsis Primary Sclersing Chlangitis Metablic Liver Diseases Haemchrmatsis inherited bld disrder that causes the bld t retain excessive amunts f irn Nn-alchlic fatty liver disease Clinical features Prtal hypertensin and its assciated cmplicatins Oesphageal varices May cause hematemesis (vmiting bld), melaena (bld in stl) + encephalpathy Treated with senstaken-blakemre tube Ascites Treatment f Liver Failure Treatment Treatment f the Underlying Liver Cnditin Remve txic drug etc Supprtive Care Preventin r cntrl f infectin Preventin r cntrl f bleeding Nutritin Early renal supprt Recgnitin r management f raised intracranial pressure Liver Transplantatin Occurs in acute liver failure with grade 3 r 4 encephalpathy Occurs in chrnic liver failure with a Child-Pugh grade f B r C (pint system used based n bilirubin + albumin levels, as well as presence f ascites + encephalpathy) 12 mnth survival rate is 60% f thse with acute liver failure and 90% fr thse with chrnic liver failure Success depends n the primary disease causing the liver failure mst cmmnly virus related r alchlic Artificial (Bilgical r Nn-Bilgical) Liver Supprt Artificial liver supprt is an attractive ptin, especially due t 46

47 The scarcity f rgans Delays in transplantatin The ptential fr full recvery, especially fr livers damaged due t paracetaml verdse It culd be a bridge t either transplant r recvery The system must Replace necessary synthetic, eliminatry and metablic functins Cunter adverse effects f necrtic liver Bilgical Apprach Invlves live hepatcytes frm human r animals The cell lines are immrtal Nn-Bilgical Apprach Bld purificatin by adsrptin and dialysis techniques The MARS system is an example Auxiliary Liver Transplant The dnr liver is placed alngside the native liver 47

48 Regulatin f functin: enteric nervus system + gut hrmnes Alimentary System 11 Dr Kevin Murphy (k.murphy@imperial.ac.uk) 1. Describe the majr features f the enteric nervus system. 2. Explain hw the autnmic nervus system and the enteric nervus system interact. 3. Describe hw gut hrmnes cntrl GI functin Intrductin - Regulatry signal systems Nervus stimulatin NT released frm neurnes innervating target cells Paracrine hrmnes released by cells in the vicinity f the target cell + reach target cell by diffusin Endcrine hrmnes released int the bld where they reach their targets via the circulatin The GIT is regulated by the nervus system (intrinsic + extrinsic), as well as paracrine + endcrine factrs Intrinsic cntrl: The Enteric NS GIT wall: cncentratin f neurnes 2 nd t nly the NCS. Rich plexus f ganglia cnnected by unmyelinated nerve fibres Functin: integratin f mtr + secretry activities (cntrl independent f CNS). Regulates: Mtility Bld flw Water + electrlyte transprt Secretin absrptin Cnsequence f enteric dysfunctin: inflammatin (ulcerative clitis, Crhn s disease), pst-perative injury, IBS, ageing (cnstipatin) Types f neurnes: sensry (respnd t variety f stimuli), mtr (innervate smth muscle, secretry cells r bld vessels), interneurns (integrate effectr utput + sensry input) Nerve Plexuses Myenteric (Auerbach s) plexus cntinuus thrughut the GIT between the circular + lngitudinal smth muscle layers. Cntrls the activity f the muscularis externa cntrl f gut mtr functin: Peristalsis during feeding Migrating mtr cmplex during fasting Submucsal (Meissnei s) plexus cntinuus between the dudenum and large intestine; in the submucsa beneath the muscularis mucsa. Senses envirnment within the lumen, and thus cntrls: Gut secretins Gut epithelial + endcrine cell functin Bld flw Minr plexi including the deep muscular plexus (within circular smth muscle) + the ganglia supplying the biliary system + pancreas NB: there is inter-cmmunicatin between the myenteric + submucsal plexuses. Mtility in the GIT Migrating mtr cmplex ccur independently f the CNS, but require autnmic input MMC is a sequence f mvements within the small intestine functin f which is t sweep the GIT clean between meals Peristalisis the directinal mvement f fd thrugh the GIT during digestin, invlving the circular and lngitudinal smth muscles; achieved by the myenteric plexus 48

49 Extrinsic cntrl: The Autnmic NS The sympathetic branch Thrac-clumnar utflw Cell bdies f pst-ganglinic neurnes in pre/para-vertebral ganglia Splanchnic nerves carry the pstganglinic fibres t the viscera. Mst d nt directly innervate structures within the GIT, but terminate n neurns in the intramural plexuses. Hwever they d directly innervate the bld vessesl f the GIT (celiac, SMA + IMA) act as vascnstrictr fibres which allw the bld supply f the GIT t act as a reservir which needed (e.g. during exercise, pumped t skeletal + cardiac muscle) NT = nradrenaline The parasympathetic branch Crani-sacral utflw Cell bdies f pst-ganglinic neurnes clse t target rgans the preganglinic neurnes synapse n ganglia clse t gut wall/directly with enteric plexi NT = acetylchline Usually reaches GIT via vagus nerve; after the transverse cln, innervated by pelvic splanchnic nerves Excitatin usually stimulates mtr + secretry activity f GIT (rest + digest) Afferent pathways Lcal + higher feedback lps present Sensry input = chem/mechanreceptrs in the wall f the GIT Lcal afferents directly feeds back t the intrinsic/enteric NS Splanchnic + vagal afferents feed back t the CNS these include the feelings f pain, nausea + satiety Paracrine + Endcrine cntrl: the Gut Hrmnes Prduced by endcrine cells in the mucsa/submucsa f stmach, intestine + pancreas Act n secretry cells in wall f GIT, pancreas + liver t alter rate f prductin/cncentratin f their secretins Sme hrmnes may act n smth muscle, e.g. GI sphincters + gall bladder Paracrine e.g. = Histamine release frm the stmach wall is key t HCl secretin frm the gastric parietal cells, and smatstatin frm the stmach can inhibit this secretin. Functins f the GI endcrine system Regulatin f mechanical prcesses f digestin Regulatin f chemical + enzymatic prcesses Cntrl f pst-absrptive prcesses e.g. assimilatin f digested fd + CNS feedback regulating intake Effects n GIT grwth + develpment 49

50 Gastrin Synthesised in gastric antrum + upper small intestine Release stimulated by amin acid peptides in the stmach, gastric digestin + vagal input Release stimulates gastric acid secretin Release inhibited by stmach ph<3 Smatstatin Synthesised in the endcrine delta cells f the gastric/dudenal mucsa, pancreas (+hypthalamus) Release stimulated by ingestin f a mixed meal Release inhibits gastric secretin, mtility, intestinal + pancreatic secretins, release f gut hrmnes, intestinal nutrient/electrlyte transprt + grwth/prliferatin I.e. acts as endcrine cyanide. Analges e.g. ctretide used t treat neurendcrine tumurs Secretin Synthesised by S cells f upper dudenum + jejunum Release stimulated by ph<4.5 in dudenum Release stimulates pancreatic HCO 3 secretin (ptentiated effect via CCK), High cncentratins inhibit gastric acid + gastric emptying Chlecystkinin (CCK) Synthesised by mst cells densely lcated in the small intestine Release stimulated by fat + peptides in the upper small intestine (independent f vagal input) Release stimulates pancreatic enzyme release, delayed gastric emptying, gallbladder cntractin + satiety Gastric Inhibitry Peptide (GIP) Synthesised by mucsal K cells in dudenum + jejunum Release stimulated by ingestin f a mixed meal, especially fat Release stimulates insulin secretin GIP receptr agnists reduce pstprandial insulin release Peptide YY (PYY) Synthesised by L cells thrughut ileum, cln + rectum Release stimulated pst prandium (after eating) Release inhibits mtility, gallbladder cntractin, pancreatic excrine secretin, intestinal fluid/electrlyte secretin, further fd intake PYY experimentally reduces a persn s calrie intake 50

51 Liver functins Alimentary System 12 Dr Kevin Murphy Outline f lecture: the liver, glucse metablism, prtein metablism, fat metablism, bile prductin, ther functins Overview f the liver Large, multifactrial rgan Functin carefully regulated t meet bdy requirements Summary f main functins: Digestin Bisynthesis Energy metablism Degradatin + detxificatin NB: all functins are carried ut by hepatcytes EXCEPT the breakdwn + recycling f RBC, which is carried ut by Kupffer cells (fixed macrphages) in the endthelial lining f the capillary sinusids The biliary system includes drainage frm ductules int the R + L hepatic duct, int the cmmn hepatic duct, which jins with the cystic duct t frm the cmmn bile duct Hepatic bld flw - ~25% resting cardiac utput Dual bld supply 20% arterial bld frm R+ L hepatic artery 80% venus bld draining frm gut thrugh hepatic prtal vein (absrbs many nutrients, except lipids which are mainly absrbed int the lymph as chylmicrns) Glucse metablism It is imprtant t cntrl bld glucse. After a meal, the levels increase and must be taken up int tissues (stred mainly as glycgen in muscle + liver) Between meals, liver glycgen breakdwn (glycgenlysis) maintains bld glucse cncentratin. Hwever a 24hr fast will depleat the glycgen stre (nly 80g). Bld glucse must then be increased by anther pathway: Glucnegenesis The prcess f synthesising glucse frm nn-carbhydrate surces Cri cycle glucse is brken dwn anaerbically in muscles int lactate. This lactate can then be used by the liver t synthesis glucse (via a pyruvate intermediate, requires 6ATP + LDH) Glucse can als be synthesis frm amin acids via deaminatin, r frm triglycerides: Alanine pyruvate glucse Triglycerides glycerl glucse Prtein metablism The liver synthesises 90% f plasma prteins (imp. Binding/carrier functins required in maintaining plasma vlume), bld cltting factrs + dietary nn-essential amin acids (via transaminatin) Transaminatin The synthesis f dietary nn-essential amin acids frm an alpha-ket acid precursr Invlves the exchange f an amin grup (NH 2 ) ne acid with a ketne grup (=O) n anther acid E.g. pyruvic acid (ket-acid) + glutamic acid (amin acid) alanine (amin acid) + α-ketglutaric acid 51

52 Glutamic acid is a cmmn intermediate Essential amin acids (lys, leu, ile, met, thr, val + phe) d nt have an apprpriate ket acid precursr Deaminatin The cnversin f an amin acid int the crrespnding ket acid by the remval f the amine grup as ammnia + replacing it with a ketne grup Occurs primarily n glutamic acid, as glutamic acid is the end prduct f many transaminatin reactins E.g. Glutamic acid + NAD + + H 2 O NADH + H + + NH 3 + -ketglutaric acid NADH can then be used t generate ATP Ammnia is txic, therefre need t be careful with the levels within the bdy fllwing deaminatin synthesis f UREA The liver cnverts NH 3 t urea invlving CO 2 (urea = NH 2 C(O)NH 2 ) Urea is very water sluble, metablically inert + nn-txic Urea is then excreted in the urine Fat metablism Fat is the main energy stre in the bdy (stred in adipse + liver tissue) When glycgen stres are full, the liver can cnvert excess glucse + amin acids t fat fr strage The fats can then be metablised as an energy surce cnverting fatty acids t acetyl-ca Acetyl-CA can then be used t prduce energy in varius frms, entering the TCA cycle Lipprteins Synthesis f lipprteins required fr lipid transprt in aqueus envirnment; cntain triglycerides + chlesterl cre, with a phsphlipid + prtein cat (stabilising the lipid) There are varius types f lipprteins depending n their cmpsitin: VLDL = lts f triglycerides (IDL = intermediate density lipprtein) LDL = high chlesterl + phsphlipids (bad chlesterl) HDL = high prtein cat Lipprteins decrease in density HDL > LDL > IDL > VLDL the lwer density = larger diameter Gd vs. Bad chlesterl Chlesteryl ester transfer prtein (CETP) shuttles chlesterl frm HDL t LDLs since a high HDL/LDL rati is imprtant in preventin f athersclersis, inhibitin f CETP is f interest t drug cmpanies Hwever mst prmising drug = trcetrapib had t stp manufacture due t large number f adverse effects. Chlesterl + Phsphlipid synthesis Phsphlipid cmpund cntaining fatty acid, phsphric acid + nitrgen cntaining base Bile prductin Chlesterl sterl nucleus synthesised frm acetyl CA (+dietary intake) Used in the synthesis f vaius cmpunds including sterid hrmnes + bile salts Bth have imprtant rle in cell/rganelle membrane structure Bile is cntinued frmed + secreted by the liver (unregulated), then stred + cncentrated in the gall bladder (hlds ~15-60ml) Secretin f bile in the liver ccurs thrugh narrw canaliculi between adjining hepatcytes int the biliary system All ther transactins (i.e. ther secretin/absrptin) ccurs via the capillary sinusids 52

53 The majr cmpnents f bile: 50% dry weight = bile salts, chlesterl, lethicin (phsphlipid), pigments (bilirubin + biliverdin), bicarbnate ins + water Separately, sme cmpnents wuld be insluble, but tgether, bile is a stable slutin Bile acids/salts Primary bile acids are made frm the xidatin f chlesterl int chlic + chendexychlic acids Carbxyl + hydrxyl grups then added s water sluble They are then cnjugated with taurine r glycine taurchlic + glycchlic acids This increases the water slubility further NB: secndary bile acids are de-cnjugated + de-hydrxylated primary bile salts invlves GI bacteria Bile salt mlecule: planar sterid nucleus; 2 phases (amphipathic) Hydrphbic face (nucleus + methyl grups) disslves in fat Hydrphilic face (hydrxyl + carbxyl grups) disslves in water Bile functins Digestin/absrptin f fats Excretin f variety f substances via GIT Neutralisatin f acid chime frm stmach Bile release Released int the ampulla f Vater (2 nd part f dudenum) during digestin Small amunts are released during cephalic + gastric phases due t vagal nerve + gastrin influence Hwever the majrity f bile release ccurs during the intestinal phase, under the influence f CCK which causes cntractin f the gallbladder + relaxatin f the sphincter f Oddi Digestin f lipids Lipids are prly sluble in water, which makes them mre cmplicated t digest. Digestin in the small intestine is a 4 stage prcess: 1) Secretin f bile (frm liver/gallbladder) + lipases (frm pancreas) 2) Emulsificatin Bile salts facilitate the emulsificatin f a fat int a suspensin f lipid drplets, increasing the surface area fr digestin 3) Enzymatic hydrlysis f ester linkages Pancreatic lipase then splits the triglycerides int 2 fatty acids and a mnglyceride at a fat/water interface Lipases cmplexes with clipase preventing the bile salts frm displacing the lipase frm the fat drplet 4) Slubilisatin f liplytic prducts in bile salt micelles Bile salts frm micelles with the released fatty acids + glycerl Each micelle has a diameter ~5nm, and cntains ~30 mlecules Hydrphilic head f bile salt in cntact with surrunding slvent, sequestering the hydrphbic tail regins with the mnglycerides in the micelle cre Absrptin f lipids Micelles present the fatty acids and mnglycerides t the brush brder (small enugh t diffuse between micrvilli). The whle micelle is nt absrbed tgether bile salts are absrbed in the ileum, but lipid absrptin is usually cmplete by the middle f the jejunum. Bile salts are transprted back t the liver fr recycling (enterhepatic circulatin) Lipid metablism Mnglycerides + free fatty acids absrbed by entercytes are resynthesized int triglycerides by 2 different pathways: 53

54 Mnglyceride acylatin (majr) Phsphatidic acid pathway (minr The triglycerides are then cmbined with prteins, chlesterl, phsphlipids + trace carbhydrate frming chylmicrns Chylmicrns are transprted t the Glgi and secreted acrss the basement membrane by excytsis t enter lacteals (lymph channels t large t enter bld capillaries) Enterhepatic circulatin Active reabsrptin bile salts in terminal ileum. In additin, de-cnjugatin and de-hydrxylatin by bacteria make bile salt lipid sluble. Lse <5% (15-35% per day) thrugh excretin Recirculate via HPV back t liver. Hepatcytes avidly extract bile salts, clearing all frm the HPV Bile salts are re-cnjugated and sme re-hydrxylated befre reuse. Bile salt pl secreted twice per meal. Bile detx + excretry functins Liver breaks dwn/inactivates sterid and peptide hrmnes. Secreted int bile fr excretin Als perfrms similar rle with variety f freign cmpunds - usually drugs Excretry rute fr excess chlesterl - lecithin (phsphlipid) allws mre chlesterl in micelles (stabilises the high chlesterl cntent). T much chlesterl may lead t gall stnes Als invlved in the excretin f bile pigments e.g. bilirubin (prduct f haem f ld RBC breakdwn in spleen) Prphyrin grup frm haem reduced t bilirubin in spleen Cnjugated t glucrnic acid in liver excreted in bile Liver disease may lead t bile pigment gall stnes Other functins Larder functins = strage Strage f fat sluble vitamins (A,D,E,K) Stres are sufficient fr 6-12 mnths except Vit K where stre is small This pses a prblem as Vit K essential bld cltting Strage f irn as ferritin. Available fr erythrpeisis Strage Vit B 12 Insufficient Vit B 12 - pernicius (megalblastic) anaemia, nerve demyelinatin Glycgen and fat stre Prtectin Resident macrphages in liver sinusids (Kupffer cells) destry pathgens that may be absrbed frm the lumen f the gut int the enterhepatic circulatin This prevents the pathgens (especially cmmn with bacterial infectins) frm entering the rest f the bdy Ca 2+ metablism UV light cnverts chlesterl t a Vit D precursr The precursr then requires a duble hydrxylatin t cnvert it int the active frm f Vitamin D The first hydrxylatin ccurs in the liver (the secnd is in the kidneys) 54

55 The esphagus + stmach Alimentary System 13 Dr Chris Jhn (c.jhn@imperial.ac.uk) Basic plan f the Gut wall The gut wall can be divided int 4 layers: Mucsa cnsists f epithelium, lamina prpria, lse cnnective tissue + muscularis mucsae Submucsa cnsists f cnnective tissue + nerve plexuses Muscularis cnsists f smth muscle + nerve plexuses Serus/adventitia cnsists f cnnective tissue (+/- mre epithelium) Oesphagus Cnduit frm getting fd frm the muth t the stmach; imprtant in cntrl f swallwing Fd cmes in thrugh the muth, the tngue frces fd psterirly t the pharynx (sft palette raised t clse nasal cavity) int the pharynx. This is under neural cntrl Where the phaynx becmes the esphagus is C5, then ends T10 (piercing the diaphragm) The esphagus passes very clse t the recurrent laryngeal nerves + the pericardium. These may be damaged in excessive esphagus extensin. Design specifically fr functin; the lining needs t be designed fr wear and tear existence = stratified squamus epithelium Nn-keratinising therefre mist Lubricated by mucus secreting gland Many layers act as prtective layer if surface layer damaged 2 sphincters mst f the pressure within the esphagus is <atm (which means fd wants t backtrack up) s these prevent this The swallwing centre within the medulla pens the upper esphageal sphincter under parasympathetic cntrl via vagus There is a fair amunt f skeletal muscle in the upper esphagus, but this decreases as it descends this leaves an element f vluntary cntrl within the upper half When fd has entered and the upper esphagus sphincter is clsed, the blus f fd is mved dwn the esphagus by peristalisis (purely under muscular cntrl, gravity has n effect) Circular muscle is majr driver f the mvement. The muscle just superir t the blus cntract, whereas the ne in frnt/inferir relaxes rhythmic cntractin dwn the esphagus If fd gets stuck half way dwn, the swallwing centre can start a wave f 2 nd peristalsis Cycle takes ~9secnds t mve fd ~30cm lng Gastr-esphageal junctin At the Z-line, stratified squamus lining f the esphagus gives way t the simple clumnar epithelium f the stmach Lwer sphincter resides here the sphincter isn t really ne as such; there are 3 cntributing mechanisms which lead t the sphincter actin The pressure difference between the abdminal esphagus + stmach Cntractin f the diaphragm As the stmach expands, it cmpresses the Z-line Heartburn the acidic cntent being ejected int the esphagus this is because the mechanism f the lwer sphincter is nt flprf 55

56 In pregnancy, the stmach is frced upwards, and the lwer esphagus is frced back int the thrax lss f pressure difference + cntractile element f diaphragm When the stmach is empty, there are gastric flds = rugae. As the stmach distends, there is nt great change in pressure but the rugae expand. This is imprtant in preventing reflux Stmach Functin = break dwn blus f fd, hld fd and release it at a cntrlled rate int the dudenum + kill parasites/certain bacteria Structure several regins: cardia, fundus, bdy, antrum + pylris The sphincters f the stmach remain clsed pst-eating fr abut 4 hurs befre it is released int the dudenum. During this perid the blus is churned steadily Secretins: Cardia + pylric mucus nly Bdy + fundus mucus, acid, pepsingen Antrum gastrin The slightly different secretry functins f the different regins f the stmach the epithelium may be slightly different All regins have mucus prducing cells mucin mps up excess acid HCl prduced by parietal cells. Endcrine cells prduce gastrin Acid prductin 2L/day, 150mM [H+] Epithelial surface ph=6-7 (neutralised by bicarbnate ins trapped in mucus) Lumen ph 1-2 Chief cell - Pepsingen prducing cell Well designed fr prtein synthesis large amunts f RER, glgi + secretin granules Pepsingen passes thrugh gastric pit int stmach Parietal cells acid prducing cell Seen in the resting state, many mitchndria (requires vast ATP t cnc H ins by 3mil X than bld very active prcess) ATP used predminantly by H/K ATPase within cytplasmic tubulvesicles Imprtant structure = internal canaliculi internal reservirs Active state tubular vesicles fuse with canaliculi, which als fuse t frm large pen reservir extending t the apical surface; H+ then diffuses ut thrugh the stmach lumen On baslateral membrane, there is a Na/K pump which pumps K int cell; this passively diffuses int lumen H+ ins generated by carbnic anhydrase (and bicarbnate ins) frm the readily available CO2 + H2O The H+ ins are actively secreted int the reservir in exchange fr K All f the bicarbnate ins are exchanged ut f the cell fr Cl entry, which als diffuses int the reservir The H+ and Cl- ins then bnd t frm HCl 56