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GastrointestinalFunction

NEUROHORMONALCONTROLOFGUTFUNCTION I.
GITractisdividedintofunctionalsegmentbyspincters,areasofhighintarluminalpressurewhichpreventrefluxofcontentsintoothersegments. UpperEsophagealSphincterseparatethemouthandpharynxfromtheesophagus LowerEsophagealSphincterseparatetheesophagusfromthestomach,whichisareservoirforingestedfoodanddigestionisinitiatedhere. PyloricSphincterseparatethestomachfromthesmallintestine,whichcompletesdigestionandabsorbsnutrientswaterandelectrolytes. SphincterofOddiseparatethepancreatobiliaryductsfromtheduodenum,whichallowstheflowofbileandpancreaticjuicesafterameal. IlleocecalSphincterseparatethesmallintestinefromthelargeintestine/colon,whichconserveswaterandstoresfeces. Internalanalsphincterandexternalanalsphinctermediatereflexactivityduringdefication. Allsphinctersarecomprisedofsmoothmuscleexceptupperesophageal&externalanalsphincterswhicharestriated&areinnervatedbytheCNS.

Sphincters

II.

SerosaSimplesquamousepithelia(mesothelium)whichsitonconnectivetissueandiscontinuouswiththeabdominalperitoneum Musclesmoothmusclehasanouterthinlongitudinallayerandaninnerthickercircularlayer;muscularismucosaliesbetweenthesubmucosa andmucosaandismostprominentintheesophagusandthecolon.Attheupperendofthegut,striatedmuscleisfoundintheoropharynxand upperesophagus;remainderissmoothmuscleEXCEPTexternalanalsphincter,whichisstriated. SubmucosasubmucosalooselayerofCTbtwncircularsmoothmuscleandmuscularismucosa;containslargerlymphatics,bloodvessels, ganglioncells,andnevercellsofmeissnersplexus;noglandsexceptbrunnersglandsofduodenum MucosavariationsintypeanddistributionofmucosalcellspresentinGIwhichreflectsthefunctionsofthesegment.

GIMorphology

III.

Innervation

ParasympatheticNervousSystem

Parasympatheticstimulationisexcitatorytosecretionandmotorfunctionofthegut. Vagusinnervatesesophagus,stomach,SI,proximalcolon,pancreas,liver,gallbladderandbileducts;80%afferentfibersinthesmooth musclewhicharesensitivetodistension;afferentsinmucosaaresensitivetoluminalconcofnutrientsandchemical;efferentsgotoentericsystem PelvicNerveaxonsfromcellbodiesinthesacralregionofthespinalcordprojecttodistalbowel.

SympatheticNervousSystem
Sympatheticstimulationisinhibitoryonsecretionandmotorfunctionofthegut;targetsincludethevascularsystem,musculatureofsphincters andtheentericsystem.Overallactivationofsympatheticisaparalysisofmotorfunctionwreducedsplanchnicbloodflow;<50%afferents.

NeurotransmissionintheANS
ExtrinsicSystemmajorNTisacetylcholine ParasympatheticandsympatheticbothreleaseAchatpreganglionfiberstonicotinicreceptorsoftheganglioncells. PSpostganglionicsitesareintheENSandalsouseAchtoactonmuscarinicreceptors. SYpostganglionicareinprevertebralganglia(celiacsup/inmesenteric)anduseNorepinephrine,whichisinhibitoryactingon&adrenergic receptorsoneffectorcellsandsuppressesAchrelease.

EntericNervousSystem
Independentintegrativesystem,whichcoordinatesGIfunctionembeddedinthewallsofhegut. Myenteric(auerbachs)plexusbetweenlongitudinalandcircularsmoothmuscle;motoractivity Submucosal(meissners)plexusbetweencircularsmoothmuscleandsubmucosa;secretion,absorption,andregulationofbloodflow Longreflexesrespondtoluminalstimuli;involveafferent/efferentextrinsicnervesthatgototheENS,prevertebralganglia,andCNS ShortreflexesrespondtoluminalstimuliandstaywithintheNES Othernonadrenergic/noncholinergic(NANC)NTs:excitatory(substancePandneurokininA);inhibitory(nitricoxide,vasoactiveintestinal polypeptide,purines) Sensoryneuronsresponsivetomechanical,chemicalandtemperature;distensionisoneofthemainstimuliforpain/discomfort.

Eneterochromaffincellsinthemucosarelease5HTinproportiontodistensionandbindstoafferentreceptorsAP 5HT3receptorantagonistsusedtocounteractnauseaandvomitingofcancerchemotherapy(ondansetron);usedintreatmentofdiarrhea dominantIBS(alosetron); 5HT4receptoragonistsusedintreatmentofconstipationdominantIBS(tegaserod)

VagovagalReflex
Function:momenttomomentadjusmentsrequiredforoptimaldigestivefunctionintheupperGItract Afferentarcvagalafferentneuronswithdifferentsensoryreceptorsconnectedwithneuronsinthenucleustractussolitarius(NTS)andthedorsal motornucleusofthevagus(DMV). TheDMVneuronsaretheefferentpathwaysfromthebraintotheENSandreleaseAchatnicotinicsynapsesexciteandtoreleasemore Ach/substanceportoinhibitbyreleasingnitricoxideofVIP.

IntegrationofNeuralControl
Level1ENSforintegrativefunctionsindependentlyofextrinsicnerves Level2PrevertebralgangliawhereperipheralreflexpathwaysareinfluencesbypreganglionicfibersintheSC Level34withinCNS;SympatheticandParasympatheticsignalsthedigestivetractinthemedullaoblongatatothegut. Level5higherbraincentersthatprovideintegrativefunctionsforlevels3and4,whichgivesahierarchyandemotionalcomponenttoGIfunction frompsychologicalstress(sympathetic/parasympathetic),hypnosis,vomiting,andpain

IV.

GastrointestinalEndocrinology

EndocrineparacrinecellsinthemucosaalongtheentireGItract;apicalportionisnarrowwithmicrovilliandextendintothelumenand containreceptorsspecifictoluminalstimuliforhormonalrelease.

MajorHormonesoftheGItract
Gastrin(Gcellsintheantrum)inresponsetodistensionofstomach,presenceofaaintheantrum,increaseacidsecretion,trophiceffectson mucosa;similareffectsasCCKandsecretin;releasedinresponsetoduodenalacidity,increasesinbicarbonatesecretionfrompancreaticducts Cholecystokinin(CCK,Icellsinduodenum)responsetofatandproteindigestionproducsinduodenum;contractgallbladder,increasesenzyme secretionfrompancreaticacinarcells Incretinsinsulinotropiceffects;responsiblefor50%insulinsecretedafterameal;keymodulatorsofinsulinsecretionandglucosehomeostasis;at higherdosesaffectgastricemptyingandacidsecretion CC:type2diabetesabnormalincretinmetabolism;decreasednutrientmediatedsecretionofGIP,GLP1anddecreasedresponsetobetacells. GlucosedependentinsulinotropicpeptideGIP(Kcells)alsoknownasgastricinhibitorypeptide;controlsfatmetabolisminadiposetissue GLP1(Lcellsinthelowerintestine)whenadministeredtoptswT2Dincreasesinsulinsecretionandimproveglucosehomeostasis;rapidly degradedbydipeptydylpeptidaseIV(DPPIV)

OtherHormones
Motilin(mcellsinlowerstomach/duodenum)fastingcontractinginthestomachandintestine VasoactiveintestinalpolypeptideNTinENStoincreaseintestinalsecretion(VIPoma)andinhibitsmoothmusclecontractility;somesecretion effectsandincreasebicarbonatesecretionfrompancreaticductcells Neurotensin,NeuropeptideY,glucagonlikepeptide1,andpeptideYY(PYY)releasedfromcellsinileuminresponsetofatandslowgastricand intestinalmotility(ilealbreak)whichcontributestothemanagementofpostprandialglucoselevels Gastrinreleasingpeptide(invagalterminalsthatinnervateGcells)increasegastrinreleasefromGcells Somatostatinandotherpeptides(dcellsinstomach)diffusethroughextracellularspacetotargetcell(paracrine);inhibitsreleaseofgastrin Ghrelin(enteroendorincecellsinupperstomach)stiulateshunger/appetite(orexigenic)

FamiliesofPeptides
2classesbasedonreceptorsandreceptormediatedactivationofsecondmessengers GastrinFamilygastrinandCCK;commonpnetapeptidesequenceatCterminal;Ca2+is2 msgr SecretinFamilyVIP,pancreaticglucagon,GIP;cAMPisthe2 msgr Potentiation2differenthormonesfrom2differentfamilieswhengiventogetherhaveagreatereffectthatsumof2responsesduetopost receptorevents
nd nd

V.

ControlofFeeding

Hypothalamus
Braindependsonglucosetomeetenergyneeds;duringstarvationcanmetabolizeketones. Ifbloodglucose<4050mg/dlpersoncanfaintorsufferfrombraindamage BraininitiatingeatingbehaviorandreleasesEpinephrineandglucagontoraisebloodglucoselevelsfromliverglycogenstores;andelicitsmeal initiationandterminationofHTneuronsregulationthatrespondtoglucose. HThasfeedingcenterandsatietycenter;destructionofthefeedingleadstostarvationanddestructionofsatietyleadstoovereating; Shorttermsignalsmood,activityofaromaandappearanceoffood Longtermsignalsgrowthandpregnancyetc

Satiety
Feedingcenterisactiveunlessrestrainedfromsatietycenter Emptystomachleadstocontractions(hungerpangs);fullleadstosatiety Mechanoandchemoreceptorssignalthepresenceandenergydensityoffoodtocontributetosatietyinthepostprandialperiod. CCKisreleasedwhenchymeentersSIandmediatesindecreaseinappetite GRPinvolvedinsatietyasbothGRPandCCKplasmalevelsincreaseafterameal; Epinephrinealsostimulatessatietycenter;nothungrywhenexercising

WeightControl
Obesitiyassociatedwithhyperplasia(#)andhypertrophy(size)ofadipocytes. Childhoodobesistybothhyperplasia/hypertrophy;adultmostlyhypertrophy Dietdecreasesthesizebutnotthenumberofcells Leptinadministrationreducesfoodintake;productofobesitygeneandhormonesynthesizedbyadipoytesthatproportionaltonumberandfat content;HTreceptorsmonitorplasmaleptinthatincreasewhenfatstoresarehightoreducefoodintakeandrestorebodyfattonormal;leptin andinsulinconcareproportionaltobodyfat.Dietaryfatandfructosedonostimulateleptinandinsulinseretion NeuropeptideY(NPY)powerfulinduceroffeedingandobesity;HTcontainsneuronsexpressingNPYinhibitedbyleptin OrexinsA&B(correspondingtohypocretins1and2)HTpeptidesimplicatedinregulationofingestivebehavior.Orexinneuronshavereciprocal connectionswithmanyareasandisstimulatedpartlybyhypoglycemiaviaNTS,whichrelaysvagalafferentsatietysignalsfromviscera;OrexinA inducesacutefeedingbutdoesnotcauseobesity; Ghrelinappetitestimulate;increasedbyfastingwhenleptinisreduced.

SALIVARYANDGASTRICACIDSECRETION I. SalivarySecretion

FunctionalAnatomy
Glandtypes MajorSalivaryGlandsdrainedbyasingleduct(monostomatic);includeparotid,sublingual,andsubmandibular(submaxillary) Parotidglandslargestandsecreteawatery(serous)fluid SublingualandSubmandibularGlandsecretseromucousfluidwithhigherconcofproteins Minorsalivaryglandsdrainedbymultipleducts(polystomatic);includelabialglandinlips,palantineglandsinpalate,lingualglandsintongue,and buccalglandsincheeks. GlandStructure Endpiecebindsaclinedbypyramidal(acinar)ortubularcells;serousormucous Myoepithelialcellsendpiecesarelinedbystellateshapedmyoepithelialcellsinnervatedbysympatheticnervoussystemandcontraction acceleratesflowofsaliva;primaryfunctiontoprovidestructuralsupporttopreventdistenionofendpieceandextravasationofsaliva Intercalatedductcuboildalepilinedbymyepicellswhichareelongatedandlieparalleltoduct. Striatedductsimplecolumnarepi;characteristicstriationsatthebasalaspectduetoinfoldingofbasementmembraneandwithmitochondriain thefolds;ioniccompositionandosmolalityismodifiedinduct. Excretoryductcolumnarepi;modificationofsecretionioniccompositionandosmolality.

CompositionofSaliva
Water InorganicConstituentsHCO3 ,K ,Phosphate(PO4 ),Na ,Ca ,Cl OrganicConstituentsMucoproteins(ABObloodgroup,mucins);Enzymes(amylase,linguallipase,ribonuclease,antibacterialagents, muramidase);
+ 3 + 2+

IonMovementintheEndpieces(acinar&tubularcells)
Primarysecretionisderivedfrombloodandisisotonictoplasma

IonMovementintheDuctCells
Reabsorptionofsodium Chlorideabsorption Potassiumsecretioninexchangeforsodium Bicabonatesecretioninexchangeforchloride Lowpermeabilityofductcellstowater Primarysecretionismodifiedbytheductstohavehigherlevelsofbicarbonateandpotassiumandishypotonic(hyposmolar)thanplasma;athigh + ratesofsecretion,theexposuretimeoftheluminalcontentstotheductcellslimitsreabsorptionofNaandClbutnotsecretionofHCO3 andK

ControlofSecretion
BothParasympatheticandsympatheticnervessimulationincreasesalivarysecretion;PShasmorecontrol PSprolonged,wateryandhighvolume SYtransient,viscous,andlowvolume

FunctionofSaliva
DiseaseStates: Pregnancy:effectofhighmineralocorticoids CysticFibrosis:linguallipaseimportant Mumps:inflammationparticularlyparotidgland

Physiological:Protective(mucus,antibacterialactionsviaHCO3 andlactoferrin)Digestion(amylaseandlinguallipase)andLubrication(mucous)

Diabetes:severehypoglycemiariggersCNStoactivatePNS Xerostomia:drymouth(sjorgrenssyndrome)

II.

GastricAcidSecretion

FunctionalAnatomy

Upper2/3ofstomachglandulararea(oxynticgland)composedoffundusandcorpus;oxyntic/parietalcellswhichsecreteacid Lower1/3ofstomachantrumandpyloric;doesnotsecreteacid;antrumcontainsGcells(gastrin)andDcells(somatostatin)=

CompositionofGastricJuice
Gastricjuiceisamixtureofthesecretionsofallthecellsinthestomach CellTypes Parietal(oxyntic)cellsH+(140mEq/L),Cl(165mEq/L)K+(20mEq/L);IntrinsicFactor;Water Peptic(chief)cellspepsinogen;water Mucouscellsmucous;HCO3 Na+K+Cl;Water AcidSecretion(parietalcells) Hydrogenimportantinkillingmicrobes,convertingpepsinogentopepsin,denaturingprotein,notfoundinalkalinesecretion;usedas anindexofparietalcellionsecretion Chloride Potassium IntrinsicFactorneededforabsorptionofcobalamin(vitaminB12) Alkalinesecretion(nonparietalcells)

Pepsinogensecretedbychiefcellsconvertedtopepsininpresenceofacid Mucouslubricatesingestedfoodandcoatssurfaceofstomachbyprovidingabarrierbetweentheacidinthelumenandtheepithelial cell. Bicarbonatealkalinetidegeneratedduringactivehydrogensecretion Sodiumthisionisnotfoundinacidsecretion;usedasanindexofnonparietalcellionsecretion Potassium Chloride

MechanismofAcidSecretion(ParietalCell)
Na/KATPasepumponbasolateralmembraneresultsinalowintracellularconcofNaandhighintracellularconcofK Kinsidethecell(10xthaningastriclumen)movesdownthegradientintothegastricjuice(lumenmoreneg); LuminalKisexchangedforintracellularH+usingenergydependentH/KATPasepumpattheluminalmembrane;importanttargetfortherapy (omeprazole/PRILOSEC);H+generatedbyformationofbicarbonateandisexchangeforKattheluminalmembrane. AlkalineTideHCO3 movesoutofthecellatthebasolateralmembranepassivelyinexchangeofCl ClmovesintothecellatthebasolateralmembraneinexchangeforHCO3 noelectricalgradient;

GastricMucosalBarrier
pHofgastricjuicecanreach12(H+conc1mEq/L) AlkalinetideproducesaraisingofthebloodpHlocally Aprotectivelayerofmucuscoatstheepithelialcells.Itcontainsbicarbonatetoneutralizeacidenteringfromthelumen;mucusisfreelypermeable toH+andHCO3butitunstirredsothereisapHgradient;acidicnearthelumenandmoreneutraladjacenttothecell. Mucosalbloodflowincreasesduringacidsecretion Cellturnoverupondamagetothesurfacethereisanimmediatereepithilizationoftheinjuredarea Entericnervoussystemdamagetomucosaelicitsprotectivereflexessuchasanincreaseinmucousbloodflow

RegulationofAcidSecretion
Endogenoussubstancesacidsecretionisregulatedbyavarietyofluminal,paracrine,neural,andhormonalfactors;physiologicalstimulants includegastrin,histamine,Acetylcholine(viavagus),caffeineandalcohol. Integratedacidsecretoryregulationproductionofacidultimatelyinvolvesstimulationoftheparietalcell;central(viavagus/ensreleaseofNT) andperipheralmechanisms(viaensandfourcelltypes): ParietalCells(fundus)containreceptorsforAch,gastrin,andhistaminewhichstimulateacidsecretion;2 msgrforAchandgastrinis nd Ca2+;2 msgrforhistamineiscAMP;histaminebindstoH2receptorsandincreasesacidsecretion. Enterochromaffinelike(ECL)cells(fundusandantrum)interfacebetweencentralandperipheralcontrolofacidsecretion;common cellulardenominatorofacidsecrtion. Dcells(fundusandantrum)secretesomatostatin;antrumsomatostainactinaparacrinefashiontoinhibitgastrinfromGcells;fundic somatostatininhibithistaminereleasefromECLcells;somatostatinreleaseisstimulatedbylowintraluminapHandinhibitedbyvagal stimulation(Ach). Gcells(antrum)secretegastrininresponsetogastrinreleasepeptide(GRP)orAchfromnerves;actinactsonECLcellstorelease histaminewhichactivatesparietalcellstoincreaseacidsecretion. Pepsin(chiefcells)releasepepsinogeninresponsetofood,Ach,andgastrin;inpresenceofacid(pH4.5)pepsinogenisconvertedto pepsinwhichdigestsprotein;digestedproteinproductsstimulatereleaseofmoregastrinwhichstimulatesparietalcellstosecreteacid untilthereisnotenoughfoodtobufferacidandpHfallsbelow3.0;AntrlaacidinhibitsgastrinreleasefromGcellsandincreases somatostatinreleasefromDcells;aspHincreasespepsinisinactivated.
nd

PhasesintheStimulationofAcidSecretion
InterdigestivePhase Basalorfastingacidsecretionisabout2mEq/hrandisproducedbycontinuouspresenceofhistamineandtonicreleaseofAchfromnerves Equivalenttoabout15%oftotalresponsetoameal CephalicPhase Mediatedbyvagusnerveandaccountsfor30%oftotalresponsetoameal; Initiatedbysmell,sight,tasteorthoughtoffood;mimickedbyshamfeeding,hypoglycemiaorintereferencewithglucosemetabolism;

VagalstimulationresultsinreleaseofAchatparietalcellsinfundusandreleaeofgastrininGcellsinantrum;vagalmediatorforgastrinreleaseis GRP(akabombesin);vagusinhibitssomatostatinfromDcells Cephalicphaseisblockedbyvagotomy GastricPhase Initiatedbyarrivaloffoodinstomach; mediatedprimarilybygastrinandaccountsfor50%oftotalresponsetoameal Gastrinreleasedinresponsetothepresenceofproteindigestionproductsinthestomach; Swalloedfooddistendsthestomachactivatingneuralreflexes;vagovagalreflexes(long)useafferentvagalfavoritesfromstomachtovagalnuclei inthemedulla;efferentvagalfibersreleaseAchandGRP;localreflexesactivatedbystretchreceptorsanduseintramuralfibersinwallofstomach. AchactsattheGcelltoreleasegastrinandparietalcellstoreleaseacid IntestinalPhase Initiatedbyarrivaloffoodinduodenumwhichisprimarilyinhibitorytoacidsecretion Accountsfor5%oftotalresponsetomealdigestedproteinsinduodenumreleasesmallamountofgastrinbyGcellsinduodenum Mostofintestinalresponseisinhibitorytoacidsecretionandmediatedbyactionsofentergastronesandtheactivationofneuralreflexesfollowing entryofchymeintoduodenum;secretin,CCK,GIP,andenteroglucagonarereleasedinresponsetospecificstimuliandinhibitacidsecretion; FactorsinfluencingAcidSecretion Vomitingprolongedvomitingleadstometabolicabnormalitiesincluding:alkalosis,hypokalemia,hypochlorhemia,anddehydration.

III.

ClinicalApplications

PepticUlcers
Ulcerdevelopwhenmucosalresistancemechanismsareoverwhelmedbyintragastricacidandpepsin;inthepresenceofacid,pepsindegrades themucusgelallowingthecelltoexposedtoacid,backdiffusionofH+mayoverwhelmtheabilityofthesurfacemucosatoneutralize Gastriculcersacidsecretionnormalordecreased;accompaniedbygastritis;severalcausesofgastriculcers: Helicobactorpyloricausativeagentofsuperficialgastritis;associatedwithgastriccarcinomaandlymphoma;colonizestheantrumand secretesureaseandtheammoniaprovidesresistancetotheacidicenvironment;acuteinfectionisassociatedwithtransient hypochlorhydria(lowacid)andchronicisassociatedwithhypergastrinemiaanddecreasedsomtastatinlevels;txincludeacidinhibitor (protonpump)andantibiotic Nonsteroidalantiinflammatorydrugsincludeaspirin,ibuprofen,naproxen,sulindac,andindomethacin;inhibitthesynthesisof prostaglandinswhichhelpdefendmucosabyincreasingmucosalbloodflow,mucoussecretion,andinhibitingacidsecretion;inacid, aspirinionizesandisabsorbedbythestomachactingasalocalirritant;damageisprimarilyintheantrum. Alcoholconclessthan8%arenotharmful;canbeabsorbedbythestomach HClconc>250mMoverwhelmthenaturalabilityofthemucosalbarriertopreventdiffusionofacidintoepithelia Stresscausesreducedbloodflow;damagetofundus/corpus;acidmayplayarole;ptssubjectedtoseveretrauma,acuterespiratory failure,increasedintracranialpressure,shock,burns,hemorrhageorsepsis Perniciousanemiaatrophyofparietalcellssonoacidandnointrinsicfactor;poorabsorptionofB12;gastritispresent Duodenalulcersacidsecretionisnormalorincreased(30%ofpt);zollingerellisonsyndrom(ZES)presentswithduodenalandjejunalulcers;ZES ischaracterizedbygastrichypersecretioncausedbyagastrinsecretingtumor. Txofulcersacceleratedbyagentsthataffectacidsecretion;smokingisdiscouragedandincreasesincidenceofulcerrelapse; Anticholinergicscnssideeffects Antacidssodiumbicarbonateandsaltsofmagnesiumcalciumoraluminum,reboundeffectasincreasedpHstimulatesgastrin secretion;Caincreasesacidsecretion;antacidsmayintereferewithotherdrugabsorptionofmanyotherdrugs H2antagonistscimetidine(tagamet)ranitidine(zantac)nizatidine(axid)&famotidine(pepcid);first3interferewithalcoholmetabolism BarrierEnhancerssucralfate(carafate)carbenoxolone(liquoriceextract)prostaglandins H+/K+pumpinhibitorsomeprazole(losec)inducessecondarygastrinemia Prostaglandinsinhibitacidandenhancemucosalbarrier(misoprostil)limitedusebecauseofcontractileeffectonGIsmoothmuscle AcidDiversionprokineticdrugsmetaclopromideerythromycine&cisapride(motilinreceptoragonists)increasegastricemptyingofacid

GastroesophagealRefluxDisease(GERD)
GERDcausedbythepresenceofacidintheesophagus PathophysiologyofGERD:reducedloweresophagealsphincterpressure(LESP);abilityofesophagustoclearrefluxedmaterial;natureandvolume ofthegastriccontents;intrinsicresistanceofesophagealepitheliumtoinjury MedicationsthatincreaseLESPareonlyminimallyeffectiveandtherapymustincludeinhibitionofacidsecretion.

PANCREATICANDHEPATOBILIARYSECRETION I.
PancreaticEndocrinefunctionlocalizedinisletsoflangerhans,whichareinterspersedthroughoutthegland PancreaticExocrinefunctionproductionandsecretionofpancreaticjuice,whichconsistsofdigestiveenzymesandbicarbonate

PancreaticSecretion

FunctionalAnatomy
PancreascomposedoflobulesboundbylooseCT;derivedfromprimitiveforgetanddorsalandproximalportionshavedifferentembryonic origins;vascularizedbythesplenicartery PNSinnervationofpancreasinputisviavagusandpostganglionicfibersreleaseAchatbloodvesselsandparenchymalcells SNSinnervationofpancreasarisesfromtheceliacandmesentericganglionandfollowsbloodsupplyintogland;norepinephrineisreleasedat vascularsmoothmusclecellsratherthanparenchymalcells Pancreaticacinarcellscontainzymogengranulesandproducethedigestiveenzymesinpancreaticjuice;centroacinarcellsaresmallthanacinar cellsandforminitialpartoftheductsystem Ductcellselaboratethefluidandelectrolytesecretionofthejuiceandformbicarbonate; Intercalatedductscuboidalcells;contributetoelectrolytesecretion;emptyintointerlobularductsemptyintotheductofwirsung Majorductductofwirsungjoinsthedistalcommonbileduct,whichenterstheduodenumatthepaillaofvater. Bothductsaresurroundedbysphincterofoddi. Somepeoplehaveaminorpancreaticductakaductofsantorini.

ElectrolyteCompositionofPancreaticJuice
Pancreaticjuiceisisotonictoplasmaatallratesduetoafreepassivemovementofwaterwithsolutes PrincipleanionsareClandHCO3andprincipalcationsareK+andNa+; Concofcationsarenotaffectedbytherateofsecretion,buttheconcofanionsvariesconsiderablewiththerateofsecretion; Increaseinbicarbonateconcisassociatedwithamirrorimagedecreaseinchlorideconcentration

SecretionofBicarbonateIons
HCO3exitsintolumenviaCl/HCO3exchange CFTR(cysticfibrosistransmembraneregulator)cAMPactivatedClconductancechannelintheluminalmembraneallowsrecirculationofCl

Secretionofproteins
PancreaticJuicecontainsmanyproteinsandenzymes,manyofwhichareinactiveproenzyme;activationoccursintheintestinallumen;also containsatrypsininhibitorwhichbindstofreetrypsinpreventingactivationofproenzymespriortoentryintotheintestinallumen Protelyticendopeptidases(trypsinogen,chymotrypsinogen,proelastase);exopeptidases(procarboxypeptidaseA/Bandproaminopeptidase) Amylolyticamylase Lipolyticprocolipase;lipase;prophospholipaseA2cholesterolesterase Nucleolyticribonuclease;deoxyribonuclease

RegulationofPancreaticSecretion
Secretinreleasedbyentryofacidintoduodenumandstimulatesbicarbonateandwatersecretionfromtheductcells;VIPalsoincreasesHCO3 andfluidsecretion,butislesspotent;releasedfromthevagusandbindtoreceptorsontheductcellmembraneactivatingadenylatecyclaseand increasesIClevelsofcAMP;alsohaveaweakstimulatoryeffectonenzymesecretion CCKreleasedbypresenceofaaandfatsinduodenum;stimulatesenzymesecretionfromacinarcells;gastrinreleasedbypresenceofprotein digestionandproductsinstomachwhichalsoincreasesenzymesecretionbutlespotent;bindtoreceptorsonacinarcellswhichincreaseslevelsof ICCa2+;alsohaveaweakstimulatoryeffectonelectrolyteandfluidsecretion PotentiationinteractionbetweenthetwodifferentintracellularpathwaysactivatedbyCCKandsecretinbindingtocellreceptorswhichresultsin anactionthatismorethanthesumoftheindividualresponses.

Nervesvagovagalreflexesareinitiatedbyentryofchymeintotheintestine;AchisreleasedinthevausandintheENS;VIPalsoinpostganglionic nerveterminals;stimulationofHCO3andwatersecretionfromductcells(byVIP)AchbindstoincreaseCa2+levels;SNSstimulationinhibitsvagal andsecretininducedsecretionandmayinhibitpancreaticsecretionindirectlybyreducingbloodflow.

PatternsofSecretion
Majorfuncofpancreaticenzyemesaidindigestionofnutrients MajorfuncofpancreaticHCO3secretionneutralizeacidfromstomachandprovideoptimalpHforenzymes; Basalfastingenzymesecretion10%;HCO312%ofmaxsecretion;duetolowlevelofAchreleasefromvagusandcirculatingsecretin Cephalicactivatedbycentralintegrationofsightsmelltasteandactofeating;mediatedbyvagusnerve,whichstimulatesenzymesandtoalesser extentHCo3andfluidsecretion(vagalreleaseofIVP) Gastricinitiatedbyentryoffoodintostomach;stimulationofenzymesecretioninducedbythevaguscontinuesandisaugmentedbytheaction ofgastrin;fluidandelectrolytesecretionisstillonlyweaklystimulated. Intestinalinitiatedbyentryoffoodintoduodenum;7080%ofpancreaticsecretoryresponsetoameal;firstbigincreaseinHCO3andfluid secretion;mediatedbyreleaseofsecretinfromScellsinupperintestineinresponsetointraluminalacid;thresholdforsecretinstimulationisapH of4.5andismaxat3.0;CCKisreleasedfromupperintestinalIcellsinresponsetopresenceofFAandpeptides;enteropancreaticreflexinvolves VagalreleaseofAchinresponsetopresenceofFAorAAintheduodenum

FeedbackControlofPancreaticSecretion(notonexam)
Increaseintrypsinandotherproteaseconcinthelumenoftheupperintestineinhibitsprimarilytheenzymecomponentofpancreaticsecretion Presenceoffatsinthelowerintestineinhibitspancreaticsecretion;involvesNPY(PYY_;helpsreturnintestinetoafastingstate Increaseincirculatingplasmaglucagon,somatostatin,andpancreaticpolypeptideafterameal;thesearepresentinendocrinecellsintheintestinal mucosainthepancreaticislets;allthreeinhibitpancreaticsecretion.

ClinicalApplications
PancreatitisassociatedwithalcoholabuseandblockageofpapillaofVaterbygallstones;pancreaticenzymesaccumulateinductovercome trypsininhibitoranddigestpancreasdestroyingfunction;associatedwithpan CysticFibrosisdefectinClsecretionduetoadefecton(cysticfibrosistransmembraneClconductance)CFTRchannelsonapicalsideof centroacinarandintralobularductcellsinthepancreasleadstoreductioninpancreaticbicarbonatesecretion;ptshaveviscoussecretionswhich blocksmallductsandleadtolocalinflammationandsubsequentfibrosisofpancreaticcparenchyma;additionaleffectislossoftissuedueto prematureactivationofproteolyticenzymes;

II.

HepatobiliarySecretion

Bilerequiredfordigestionandabsorptionoffatsandforexcretionofwaterinsolublesubstanceslikecholesterolandbilirubin;livernormally secretes6001200mlofbiledaily

CompositionofBile
Bileiscomposedof:NaCaHCO3higherthanplasmaandCllowerthanplasma;osmolalityisabout300mOsm/Kgandduemostlytoinorganicions Bilecontainsorganicsubstancesincluding:bileacids,bilepigments,cholesterol,phospholipids,andsmallamountsofproteins(IgA,albuminand glycoproteins)estrogens,androgens,somedrugsandcarcinogensareexcretedintothebile Bileacidsmajororganicsolutehandledbyhaptocytesandsecretedintothebileasbilesales(pKbelowpHofbile);mustbeconjugatedwglycine andtaurineogholateandchenodeoxycholate(2:1)tobesolubleinwater;bilealsocontainssecondarybilesaltsconjugatedbybacteria deoxycholateandlithocholate;mostbilesaltsarepresentasmicelles. Phospholipids(lecithin)solubilizedinmicellesbeforesecretioninbileandhelpbilesolubilizecholesterol Cholesterolpresentinsmallamountsandmustbesolubilizedbybilesaltmicellesbeforeitcanbeexcretedinbile;biliarysecretionofcholesterol isimportantinregulationofcholesterolstores;] Proportionofphospholipids,bilesalts,andcholesterolisimportantinsolubilizingcholesterol(15%cholesterol30%lecithin55%bilesalts);natural decreaseinlecithinorbilesaltsorincreaseincholesterolresultsinbilethatissupersaturatedwithcholesterolprecipitateandformgallstones

BileFormation
Bileformedbyhepatocytesandductalepicells;secretedintobilecanaliculi;modifiedbyintraandextrahepaticbiliarysystem;storedingall bladder;deliveredintheduodenumthroughpapillaofVater Bilesaltsmostlyfrombloodinsteadofdenovosynthesis;conjugatedbileacidsboundtoalbuminareretakenupbyNa+dependentprocessby hepatocytes;extremelyefficientlyandareboundtoacarrierproteinandsecretedintobile Bilepigmentunconjugatedbilirubiniscaredfromthesplenicreticuloendothelialsystemboundtoalbumin;takenupbyhepatocyteinefficiently; bilirubinishydrophobicandisboundtoligandinandsenttotheERwhereitisconjugatedwithglucuronicacidtomakeitwatersoluble;senttothe intestinewhereconjugatedbilirubin(orange)isdeconjugatedbybacterialmetabolismtourobilinogen(yellow)whichreabsorbed(20%)and excretedbythekidneyortakenbacktotheliverviaenterohepaticcirculation;theremainder(80%)ismetabolizedfurthertostercobilin(brown) andexcretedinthefeces.

FattyAcidtakenupbyaseparatetransporterboundtoFAbindingproteinandsecretedaslecithins Chylomicronuptakeintestinalabsorptionoffatyieldsdigestionproductsincorporatedintocylomicrons;absorvedvialactealsandsubsequent hydrolysisoflipoproteinsyieldschylomicronremnantsandfreeFAs;remnantsaretakenupbyreceptormediatedendocytosisbyhepaticytesand aredigestedintoavarietyofproducts.

RegulationofBiliarySecretion
Biliarysecretoryvolumeandamountofbileinsecretionareregulatedseparately;canalicularbileformationisanosmoticflowofwaterinresponse toactivesolutetransport BileAcidDependentBileFlowquantityofbileslatssecretedbytheliver;directlyrelatedtoamountreabsorbedbytheenterohepaticcirculation; bilesaltsandacidsaresubstancesthatincreasebileflow(choleretics)byprovidingosmoticforceforwaterandsolutestofollow;synthesisand secretionofbileacidsisnotunderanydirectneural/hormonalcontrol;CCKincreasesbileflowbyreleasingbilefromgallbladder Bileacidindependentbileflowamountoffluidcontainingwaterandelectrolytessecreteddailybytheliver;fromtwosources:canalicularcells contributesolutes(Na+)andwaterfollowspassively;ductalcellsmodifybileasitpasses(HCO3)controlledbysecretinwithCFTRchannelsinvolved andsomatostatininhibitssecretion

EnterohepaticCirculation
EnteroheapticcirculationrecirculationofbilesaltsfromlivertoSIanbackagain;principalsourceofbileacids;necessarybecauseofthelimited poolofbilesalts UnconjugatedbileacidsarelipidsolubleandcanbeabsorbedanywherealongtheSI;9095%ofconjugatedbileacidsareactivelyreabsorbedin theterminalileumbyNa+dependenttransportprocess;therestexcretedwithfeces. Totalcirculatingpoolofbileslats~3.6gandabout48gofbilesaltsareneededtodigestamealsopoolcirculatesabout2x/mealor68x/day Therateofdenovobilesaltsynthesisisdeterminedbytherateofreturntotheliver;~0.2/0.4g/daytocompensateforfecalloss

Gallbladder
BileInGBcontainshigherconcofbileacids,phospholipidsandcholesterolduetoreabsorptionofwaterandelectrolytes GBstores2050mLandconcentratesbile515foldduringtheinterdigestiveperiodandemptiescontentsintotheduodenumduringdigestion; distensibleduringdigestionandsphincterofOddiisclosed;Bileisconcentratedandacidifiedbythereabsorptionofwaterbytheasmoticgradient producedbytheactiveabsorptionofNa+ClandHCO3 GBcontractionandsphincterofoddirelaxationoccursinresponsetoVagalstimulationduringcephalicphaseandviavagovagalreflexesduring thegastricphase;entranceoffatandproteindigestionproductsintotheduodenumintheintestinalphasestimulateCCKwhichisamajor stimulantforGBcontractionandsphincterofoddirelaxation Cholecystectomybileemptiesslowlybutcontinuouslyintotheduodenum;digestionoffatsisnormalbuthighfattymealsshouldbeavoided

ClinicalApplications
Gallstonesformedin130%ofwesternpopulationthough20%producesymptoms;causesincludetoomuchabsorptionofwaterfrombile,too muchcholesterolinbile,inflammationoftheepitheliumofbileducts. Majorityofgallstonesarecomposedofcholesterol;whenmicelleproportionsarealteredcholesterolcrystallizestoformradiolucentstones(dark onxray);stasisintheGBcontributestostoneformation;femalehormonesreduceGBcontractionsleadingtoincreasedresidencetimeofbileinGB Txinvolvesincreasingbileacidpool(oraladminofbileacids)ordecreasecholesterol(oraladminofsolublefibertobindcholesterol) Bilepigmentgallstonescomposedofcalciumbilirubinatearelesscommonandformedbyinjectionofbiliarytreeandleadstobacterial deconjugationofconjugatedbilirubinwhichinsolubleinbileandprecipitatesandleadstoformationofradiopaquestones. Jaundiceyellowingofskinduetoaccumulationofbilirubinwithintissuesandblood ExcessproductionofbilirubinasaresultofexcessiveRBCdestructioninhemolyticanemia Obstructionofbileductsorlivercellspreventingsecretionofbilirubin Bilirubinmetabolismdefect: Physiologicaljaundicecommoninnewbornandduetoanimmaturityofseveralstepsinbilirubinmetabolismproducingunconjugated hyperbilirubinemia Gilbertssyndromebenignhereditary(autosomaldominant)hyperbilirubinemia;mostcommonformofhereditarydisorders; associatedwithdecreasedbilirubinclearance;50%alsohavehemolyticanemia;normalbileacids;bilirubinbuildsupinhepatocyteand increaseinrefluxofunconjugatedbilirubinintoplasma CriglerNajjarSyndromecongenitalform(autosomalrecessive)ofnonhemolyticjaundiceduetoabsenceofglucuronidetransferase; bilirubinbuildsupinhepatocyteandincreaserefluxofunconjugatedbilirubinintoplasma;pathologyduetoabsence(typei)or decreased(typeii)UDPtransferase. Dubinjohnsonsyndromefamilialformofnonhemolyticjaundiceduetoinhibitionofcanalicularexcretionofbilirubinbutnotbileacids; characterizedbypresenceofabrowncoarselygranularpigmentinhepatocyes

Threeclassesofhyperbilirubinemia: Unconjugatedgilbertssyndromeorhemolyticanemia Conjugatedcholestasisandacutehepatitis Mixedcirrhosiswherethereishymolysisaswellasportosystemicshunting

GASTROINTESTINALMOTILITY I. GastrointestinalSmoothMuscle

StriatedvsSmoothMuscle
Striatedcontractswithneuralinput;voluntary;excitationcouplingcomesfromincreaseinICCa2+stress;troponininitiatescontraction Smoothcancontractinabsenseofneuralinput;excitationcouplingcomesfrominfluxofECCa2+;highsurfacetovolratiofacilitatesinfluxandIC diffusionofCa2+;lackstroponin;contractionoccursviacalmodulinmediatedactivationofmyosinfilaments. CytosolCa2+increaseswhichbindstocalmodulin; Calciumcalmodulincomplexbindstomyosinlightchainkinaseandactivatesit MLCKphsophorylatesmyosinlightchains(relax)whichformcrossbridgeswithactin(contraction) ThenATPdissociatesactinandmyosin Ascytosoliccafalls,rateofdephosphorylzaionofmyosinbymyosinlightchainphosphataseexceedsphorphorylationleadstorelaxedstate Ifcyclingoccurs,itcontinuesthemaintananceofcontraction.

RestingMembranePotentialinSmoothMuscleCells
RestingmembranepotentialofGIsmoothmuscleis~60mV;circularsmoothmusclehaveslowwaveswhicharemyogenic. Basalelectricalrhythmisslowwavefrequency;BERisresponsiblefortiming,speed,anddirectionofGIcontractions;notallwavesproduce contractions;controlledbyinterstitialcellsofcajal. ICCareinterposedbetweenmotorinnervationandcircularsmoothmusclesinthestomachandSI,bothontheoutersurfaceandwithin. Contractionsspikepotentialsduringdepolarizationphasesofslowwaves;determinedbynetneuralandmechanicalinputtomuscleattopofthe slowwave;spreadofcontractionisdeterminedbynexuses;amplitudeofcontractiondependsonnumberofspokepotentialswhicharedependent ondistensibility,NTandhormones

NeuralandIntracellularCommunications
Longitudinalmusclethinnerwithlessnexuses;primarystimulusisexitatoryviaAch(vagus)forcontraction Circularmusclethickerwithabundantnexuses;manyNTsinvolved,whichspreadvianexusesasanelectricalsynctium.

ContractionsinSmoothMuscle
Slowwavesdontinitiatecontractions,butgovernfrequency; Spikepotentialsleadtocontractionsonlyduringdepolarization; Amplitudedependentonnumberofspikepotentials,whichdependonmusclestretch,NT,andhormones; Musclestretch,nt,andhormonesdonoteffectBER.

NeuralControlofContractions
Neuralcontroltocircularsmoothmuscleisinhibitory(VIPNO);ifthereisnoinhibitoryeffectthentherewouldalwaysbecontraction IntegratedmotorGIfunctionrequiresneuralcontrol.

TypesofGastrointestinalContractions
TonicContractionfundusofstomach,GB,sphincters;composedofsmoothmuscle;hastone;noBER;caneitherrelaxorcontractbasedonNT. Segmentalcontractioncircularsmoothmuscle;maxnumberdeterminedbyBER;facilitatemixingandproducesanetmovementaborallydueto gradientintheSI. Peristalticcontractionspropulsivemovementsthatrequirecoordinationoflongitudinalandcircularsmoothmuscle InhibitedorabsentGIhasquiescentperiods

Reflexes
ReflexesservetocommunicateinfobetweendistantsegmentstocoordinateGImotility; ShortentirelyinENSonly

LongSNSguttoprevertebralganglia LongSNS/PNSguttospinalcord/brainandbacktogut;vagovagalreflexes.

II.

GastricMotility

MotorFunctionsoftheStomach
Storagereservoir Mixingpreparationofingestedmaterialandformationofchyme Emptyingdeliveryofnutrientstothesmallintestine

GastricMotorPatterns

Fastingmigratingmotilitycomplex(MMC)isacyclicmotorpatternintheinterdigestiveperiod;dependsonENSsystem;originatesinlower2/3 ofstomachandendsinterminalileum;comprisedofthreephases: PhaseImotorinactivity Phaseiiintermittentmotoractivity Phaseiiihousekeeperregularintenseandrepetitivecontractions;clearstheSIofundigestedresidue,mucous,sloughedcellsandprevents bacterialovergrowth;AchactivatesM3receptorsonMcellswhichsecretemotilin;housekeepercontractionsareinhibitedby5HT3antagonists FEEDINGINTERRUPTSTHEMMC Postprandial ReceptiveRelaxationvagallymediated;upper1/3ofstomach(tonicmuscle)relaxesandallowsanincreaseinintragastricvolumewithlittlerisein pressure(compliance);VIPandNOinvolved;initiatedupondeglutitionandesophagealperistalsis;stretchreceptorsinstomachareapartofa vagovagalreflextoinhibittheefferentdischarge;impairedbyvagotomy Inhibitionofcontractilityintheproximalstomachpredominatesduringdeglutition;afterentryoffoodslowsustainedcontractionsbeginnot controlledbyslowwaves;reflexivelymediatedbyAchinresponsetodistension;raisepressureandgraduallyforcecontentstodistalstomach Propagatedperistalticcontractionsoccurindistalstomachandmaxfreqiscontrolledbyslowwaves(3/min);ariseinmidcorpusandspread distallytopropelfoodtowardspylorus;terminalantrumcontractsandpyloruscontractsalso;liquidsandsmallparticlespass;food>0.2mare retropulsedandundermixingandgrinding(trituration);constrictionofpylorusuponcontractionofterminalileumpreventsrefluxofduodenal contentsintostomach.

GastricEmptying
Gastricemptyinggovernedbystomachandduodenum;stomachactsprimarilytopromotegastricemptyingbycontractionswhichmovecontents distally;duodenumgenerallyopposesgastricemptying Volumegreaterintragastricvolumefastertherateofgastricemptying(uptoacertainpoint);increaseinintragastricpressureworksimilarly ParticleSizeliquidsemptyfasterthansolids;undigestiblesolidsremaininthestomachuntilphaseIIIofMMC CaloricContent/MealCompositionduodenumcontrolsthedeliveryofcaloriesregardlessofthesource;fatemptiesslowest. Osmolalityisotonicsolutionsemptythefaster pHlowerpHslowergastricemptying Hormoneshormonesreleasedinresponsetofoodentryintostomachandduodenum(gastrin,secretin,CCK,GIP)slowdowngastricemptying andincreasestrengthofgastriccontractions NeuralMechanisms(enterogastricreflex)chemicalormechanicalstimulationofduodenalmucosainhibitsgastricperistalsisandslowsgastric emptying Vagotomyimportantaffectsongastricemptying;increaseingastricemptyingofliquidsduetoimpairedrelaxationoftonicstomachanddecrease ingastricemptyingofsolidsduetoreducedforceofantralcontractionssotriturationisprolonged.

Vomiting
Vomitingforcedexpulsionofstomachandintestinalcontents;precededbynausea,salivationandretching;initiatedbydirectactivationof vomitingcenterinmedullaorchemoreceptortriggerzonebydrugs(apomorphine)inthebrainstem;duetoinjury,increaseinintracranialpressure orafferentfibersrespondingtopsychicstimuli;whendirectlyactivateditproducesprojectilevomitingunaccompaniedbynausea; MechanicsofVomitingDuringretching,theduodenumandantrumcontractionforcingtheircontentsintotherelaxedbodyofthestomach (antiperistalsis);vomitingbeginswithadeepinspirationfollowedbyclosureofglottis,loweringofintrathroacicpressure;larynxandhyoidbone arepulledforwardopeningtheUES;diaphragmandabmusclescontract,increasingtheintraabdominalpressureandthelargegradientpressure betweenthoraxandabdomenopenstheLES;gastriccontentsexittheesophagusandmouth.

ClinicalCorrelations
Dysrhythmiaselectricalactivityoftheantralpumpcanberecordedbyelectrogastrogram;tachygastric>3/minBER;bradygastric<3/minBER DelayedGastricEmptying/Gastroparesisusuallyaccompaniedbygeneralizeddiabeticneuropathy,ketoacidosisorhypercalcemia;MMC impairedorabsent;nasusea,postprandialfullness,andearlysatiety;pyloricstenosismostcommoncauseininfants;prokineticdrugsincrease gastricemptyingwithagentsthatactonmotilin(erythromycinanalogs)acetycholine(metaclopromide)5HT(ondansetroncisapride)receptors IncreasedGastricEmptyingpyloricsphincterincompetencemaycomplicatecertaingastricsurgeries;zollingerellisonsyndromecausedby gastrinsecretingnonbetaislettumorofthepancreaswhichleadstohyperacidityandrapidgastricemptying GastricSurgerydistalsurgicalgastrectomiesareperformedastreatmentforacidpepticdisease;variableportionofthedistalstomachincluding pylorusisremovedandremainingstomachisanastomosedtoduodenum(billrothi)orjejunum(billlrothii);attachmenttobillrothiiissogastric contentscanbypassreceptorsintheduodenumthatarenormallyslow.

III.

SIsmainfunction:absorption

IntestinalMotility

Contractileactivityservestomixchyme,facilitatingexposuretoabsorptivesurfaceandtomoveitfromtheduodenumtothecolon;~2hrs

GastricvsSmallIntestinalMotility
BERisfasterinintestine Peristalticwavesdonottravelentireintestine Thereisnostorageoffoodinthesmallintestine

PacemakerActivityalongtheAlimentaryTract
Stomach3/min;Pacemakercells(cellswithhighestfrequencyofdischarge)locatedinthemidcorpusalongthegreatercurvature StepwisedeclineofBERalongtheSIrangingfrom12/mininduodenumto89/mininileum Upperintestinethepacemakercellslienearentryofthebileduct;musclecellsinthedistalregionshavealowerfrequency;toassureaboraltransit

SmallintestinalMotorPatterns
FastingPatternsapproximatelyevery90minanMMCtravelsataspeedof5cm/sec;theshortestperiodwthestrongestcontractionsisphase3 FedPatternspostprandialactivityhasirregularcontractionsofshorterduration;mostprominentareafterthemealaresegmentation contractionsthenperistalticcontractions Vagusneededtomaintainthefedpattern Presenceoffatinileuminducestheilealbreakwhichslowsgastricemptyingandintestinaltransittoallowmoretimeforabsorption;hormones involvedareNPYandPPY,andGLP1

TypesofContractions
Segementationchymeisdisplacedinbothdirectionsbycircularsmoothmuscle;backandforthmotionallowsmixingwithdigestivejuicesand contactwiththeabsorptivesurface;BERgradientallowsforaboraltransit Peristalsiscontractionsoccuratadjacentsegmentsinanoraltoaboralsequencetopromoteanetpropulsion;requiresbothlongitudinaland circularsmoothmuscle(peristalticreflex);mediatedbytheENS;propagateonlyshortdistances;mainexcitatoryisACh,inhibitoryVIP/NO

ClinicalApplications
Abrnomalitiesinspikeactivity,slowwavefrequencyorvelocityandgenerationoftheMMCcanleadtonausea,vomiting,diarrhea,orconstipation Ileusstateofnomusclecontractivity;BERstillpresent,butlittleornospikeactivityduetotheintrinsicinhibitoryneurons;producedbyirritation ofperitoneum;postoperativeileuspartlyduetosympatheticreflex Spasmofcircularmuscleisoppositeofileuswithnoactivityofinhibitoryneurons;syncytialpropertiesareinherentlycontractingproducingmax contractions. Hyperthyroidismoftenaccompaniedbydiarrhea,BERisincreased;decreasedBERisdecreasedinhypothyroidism Pregnancyassociatedwithconstipationduetoincreasedprogesteronelevels

IleocecalJunction
Ileocecaljunctionboundarybetweenthesmallandlargeintestine;hasasphincterofsmoothmuscle,tonicallycontracted;distensionofthe ileumrelaxesthesphincteranddistensionofthecoloncontractsitandinhibitscontractionintheterminalileum;valvefunctionstopreventreflux ofcoloniccontentsintoileum

IV.

Colonfunctionstoabsorbwaterandelectrolytesandtostoreperiodicallyeliminatefeces

MotilityoftheLargeIntestine

Anatomy
Muscles Longitudinalmuscleisnotcontinuousaroundthecircumferencebutismadeofthreebandscalledtenaecoli Haustraaresacculationsfromthelongitudinalmuscle;formedbytheelongationofthecircularmusclesothattheinnerlayerbulgesoutbetween thetenaecoliwhicharetheninterruptedbythetightbandsofcircularmusclecalledplicaecirculares Nerves Intrinsicnervesinthecolonexertanetinhibitoryinfluence RightsideofthecolonreceivesPSinputfromvagusandpelvicnerves; Vagalstimproducessegmentalcontractionsinproximalcolon Pelvicstimproducespropulsivecontractionsindistalcolon Splanchnicnervesinnervatetherightcolonwhilelumbarnervesinnervatetheentirecolon PSstimulationleadstocontractionwhileSNSstimleadstorelaxation.

SmallvsLargeIntestinalMotility
ColondoesnothaveanMMC ProximaltoDistalgradientisabsentincolon Transitincolonisslower(days)thaninSI(hours) Colonhasastoragefunction Massperistalsisisobservedincolon

SlowWaveFrequency
BERgovernscoloniccontractionswhilspikeactivitycontrolsamplitude;BERisslowestneartheileocecaljunctionandincreasesuntilmid transversecolon BERislessinrightcolonandproduesoradpropulsionofcontents;promotesadelayintransitofchymeandmixingrequiredforfinalabsorption; BERfortheremainderofthecolonisaboutthesamewithnoBERgradient

TypesofContraction
Haustrations(contractionsinthecolon) MixingmovementsmostfrequentandoccurintheRcolon;withnonetmovement,mostlymixing Haustralmigrationresultsinnetmovementofchymeaborally; Massmovementleastfrequentpattern;movescontentsgreatdistances

EffectofFeedingonColonicMotility
Colondoesnothaveperiodsofinactivity;noMMCinterdigestivepatternsincecolonisrarelyempty Feedingincreasesthenumberofhaustrations,initiatesmassmovementanddecreasesmixingincolon.Defacationoccursafterameal;increasesin contractionsmovecontentsthroughoutthecolontomakeroomforentryofchymefromtheileum; GastrocolicreflexStimulationofmassmovementfollowingameal.

AnalSphincters
Internalanalsphinctersmoothmuscle;tonicallycontracted;activationofPSNrelaxesIASviaVIP/NOandactivationofSNSconstrictsit Externalanalsphincterstriatedmuscle;voluntarymuscle;innervatedbypudendalnerve;innervationisexcitatory

Defecation
Defecationcomplexactinvolvingleftcolon,rectum,analsphinctersandstriatedmusclesofpelvicfloor,abdowall,anddiaphragm;both voluntaryandinvoluntaryreflex Reflexactivityrectumnormallycontainslittlefecalmatter;aftermassmovement,facalmaterialentersrectum,initiatedbymilddistensionand activatesrectrosphinctericreflexwhichrelaxesIASandelicitsurgetodefecate;MilddistensionofrectuminducesacontractionofEAS; Continenceurgeisdelayed,rectumthenrelaxestoaccommodatetheincreasedvolumeandIASregainstoneandeasrelaxes. VoluntaryactivityinresponsetomilddistensionvoluntaryrelaxingoftheEAS;defecationisfacilitatedbyvoluntarycontractionofabdomuscles (valsalvamaneuver);inresponsetoincreaseddistensionofrectum,defecationcanbepreventedbyvoluntarilycontractingtheEAS

ClinicalApplications
Diverticulardiseasedesignatesthosediseasesassociatedwithherniationofmucosaandsubmucosathroughmuscularispropria;mostcommon colonicdisorder;mostlyelderlypeopleinthesigmoidcolon;associatedwiththickeningofringsofcircularsmoothmuscleincreasesinluminal pressureandcausesdiverticula;consequenceofperforationofmucosaindiverticulum Aganglionosishirschprungsdiseaseorcongenitalmegacolon;resultofabsenceofintrinsicinnervationofcolon;usuallyonlyashortsegmentof colon;nosuppressionofmyogenicactivityofsmoothmusclessoitiscontinuouslycontracted InflammatoryBowelSynrome(IBS)patientswithalteredowelfunctionandabdopaininabsenceofanydetectablestructuralabnormality InflammatoryBowelDisease(IBD)patientsincludingthosewithulcerativecolitisandcrohnscolitisdiseasesofthemucosabutfrequentlyhave symptomsconsistentwithalteredmotility;crohnsdiseaseisdistinguishedfromulcerativecolitisbtransmuralinflammationversusinflammation confinedtothemucosaandthemorefrequentpresenceofanallesions ColonicCancermostimportantdiseasewithregardtomorbidityandmortality;producesintestinalobstructionlateinthecourse;carcinomaand polypsaremostfrequentlyfoundinrectum,sigmoid,anddescendingcolon;bleedismostcommonpresentation Incontinencedamagetosphinctericmuscle,neuromusculardiseaseoralteredrectalcompliance,psychiatricdisorderscanalsoaccompany incontinence.

ELECTROLYTEANDIONTRANSPORTNUTRIENTABSORPTION I.
MainfunctionoftheSmallIntestineistheabsorptionofwater,electrolytesandnutrients

WaterandIonTransportintheSmallIntestine

Terms
ActiveTransportagainstachemical/electricalgradient;requiresenergy;carriermediated;subjecttocompetitiveinhibition PassiveDiffusionwiththechemical/electricalgradient;noenergyrequired;notcarriermediated;nocompetitiveinhibition FacilitatedDiffusionsimilartopassivediffusionexceptcarriermediated;withchemical/electricalgradient;subjecttocompetitiveinhibition Endocytosisprocessakintophagocytosisandsurroundedbyouterplasmacellmembrane;mostlyoccursinneonatalperiodandalsousedin uptakeofantigens

HistologyofSmallIntestine
SIabout300cminlength;hasalargesurfaceareaforexposureofluminalcontentstoabsorptivecells; SIincreasesSA:plicaecirculares(3x)induodenumandjejunum;villiandcryptsonmucosalsurface(10x);tipscoveredwithmicrovilli(600x) TypesofEpithelialcellsinSI:enterocytewithmicrovilliandbrushborderwithdigestiveenzyme;gobletcellsprominentinterminaljejunumand ileum,secretemucustolubricateandprotectmucosa;GALTincludespeyerspatchesMcells,andintraepitheliallymphocytes

WaterTransport
2litersoffluidthatgoesintotheintestineisingested;approximately8literscomesfromendogenoussecretionsofsalivaryglands,stomach, pancrease,andintestines;approximately98%ofthewaterandelectrolytesareabsorbed WatertransportinSIandcolonispassiveanddependsonseveralfactors: Locationalongthebowelmostvolumeabsorbed(~5.5L)isabsorbedinduodenumtojejenum;theileumandcolorectalabsorbabout2 and1.3L;distalsegmentsareintrinsicallymoreefficientduetotheirlargeporesizeandlowerresistanceintightjunctions LuminalOsmolalitychymeisadjustedtoplasmaisotonicitybythenetsecretionornetabsorptionofwateracrossthemucosa Rateofsolutetransportsegmentsdistaltoduodenum;chymeisisosmotictoplasmaandwaterabsorptioniscoupledtosolute transporteithertranscellularlyorparacellularlyduetotheactivetransportofNaoutofthecellswhichdrawswater.

SodiumTransport
Naabsorptionoccursinvilluscells;bothactiveandpassive;passivemovesNabygradientcreatedbybasolateralNa/Kpump;sodiummovement pullswaterpassivelyandpullsothersolvesbyconvection;basolateralNa/KATPasepumpprovidesenergytotransportionsagainstlargeEC gradients;andchannelproteinsprovideselectivemembranepermeabilitytoionslikeNaandCl AllmechanismsforNaabsorptiondependonNa/Kpump,whichrequiresenergyandpumps3Naoutforevery2KtocreatealowICNaconcand negativeelectricalpotentialdiff;Naentersalongitsgradientandexitrequiresenergyforpump. SubstratecoupledtransportabsorptionofwatersolubleorganicsolutesarecoupledtoNatransport;hexosesugars,certainaas,conjugatedbile salts,andwatersolublevitamins;carriermoleculesinbrushbordercouplesentryofNaandorganicsoluteintocellthrough2`activetransport; organicsoluteexitscellbycarriermediatedfacilitateddiffusion. ElectroneutralTransportofNaintheIleumnonettransferofcharge;involvestwoneutralcountertransportNa+/H+andCl/HCO3exchange; inhibitedbycAMPandincreasedICCa2+; Natransportalsooccursviapassiveabsorptionsecondarytowatertransportbysolventdrag/convectionthroughlateralspacesandtightjunctions

OtherIonTransport
InSIKisabsorbedpassivelybysolventdragsecondarytowaterflowandKissecretedincolon CLtransportisaresultofneutralNaClabsorption;CLcanmovebetweencellsbysmallgradientbetweenlumen(neg)tointerstitium(pos) Ca2+activelyabsorbedinproximal(duodenumandjejunum)SIbymembraneboundcarrieractivatedbyaVitDderivative;entersenterocyteand isboundtocalciumbindingproteinandactivelytransportedacrossbaslateralmembrane IronAbsorptionproximalsmallbowel;bindstoreceptorinbrushbordermembraneandbindstoapoferritin(ironbindingprotein)andforms ferritin;inordertoexititdissociatesfromferritinandbindstoICcarrierproteintobetransportedoutofcell;inintestinalinterstitum,ironis transportedtoplasmabytrasnferrin(globulin)

II.

IntestinalSecretionandIonTransportintheColon

FluidSecretion
Fluidsecretionthroughintestineisaniondependent;ClissecretedbycryptcellsandexitsbyCFTRcannelsandisregulatedbychangesinICcAMP; SecretionofWaterandElectrolytesareinducedbyseveralmechanisms: ActiveAnionSecretionnormalresponseortobacterialtoxin(cholera),bilesaltsandhormones;mediatedbyriseinICcAMP HighLuminalOsmolalityprimarymechnisminproximaluodenum;responsibleforwaterretainedinlumenwhensolutesarepoorly absorbed(lactoseintolerant) IncreaesdInterstitialhydrostaticPressuresecretoryfiltration,accompaniedbyluminaldistension(bowelobstruction) DecreasedSoluteAbsorptioninhibitionofneutralNaCltransportinresponsetohormonesorcholeratoxin;riseinICcAMP;incholera transportofglucoseisnormalandisusedtotherapeuticallytoincreasewaterandelectrolyteabsorption **manyagentscausenetfluidsecretion:increaseICcAMP,ICCa2+,orICCGMPwhichacttoincreaseopeningofCFTRchannels ABSORPTIONISDRIVEBYNA;SECRETIONISDRIVEBYCHLORIDE.

WaterandElectrolyteTransportintheColon
Colonabsorbswater,Na+andClandsecretesK+andHCO3 PoresizeissmallerandresistanceishigherinColonthanSI;nopassiveabsorptionofNabyconvection Activetransportofnutrientsnotpresent ColonabsorbsNaagainstahigherconcgradient; Mineralocorticoids(aldosterone)increaseNa+absorptioninthecolon;glucocorticoidsincreaseNa+absorptioninColonandSIbyNaCLabsorption Colonabsorbsabout1.5L/day;diarrhearesultswhenfluidentryexceedsmaxabsorptivecapacityof4.5L/dayduetofluidmovementinSI/colon ElectrolyteTransport Na+absorptionelectrogenicduetoelectrochemicalgradientgeneratedbyNa/Kpump;colonabsorbs~99%ofallNa+presentduetosmaller poresandhigherresistancewhichmakesitsoefficient;aldosteroneincreaseNa+absorption K+secretionenhancedbyaldosterone ClabsorptionpassivelyfollowsNatransportorcanbeexchangedforHCO3vianeutralcarrier

III.

ClinicalApplications

MechanismsofDiarrhea
Decreasedabsorptionsuppressedorimpairedabsorptionofelectrolytesandfluid;osmoticallyactivesolutesinluemn;increasedtransitofchyme reducingcontacttimeforabsorption IncreasedSecretionstimulatedionsecretion;secretionfromcryptcells

ClinicalDiarrhea
ExterotoxinsheatstableEcoliincreaseCGMPandcholeratoxinincreasesICcAMP;bothinhibitneutralNaClabsorption CongenitalChloridorrheadefectiveabsorptionofNaClduetoimpairedfunctionofCl/HCO3exchanger Osmoticdiarrheaexcessofunderabsorbedosmoticallyactiveparticles;lactoseintoleranceandmagnesiumhydroxideinantacids Excessbilesaltsduetoilealmalfunctionfrominflammationorresection;bilesaltsentercolonandstimulatesecretionoffluidandelectrolytes; cholesterolbindingdrugsleadstoincreasebilesaltsincolon Ulcerativecolitisinflammationofthecolonaltersabsorptiveabilityofmucosa;exacerbatedbyincreasemotility HormoneproducingtumorsVIPoma,WHDAsyndrome,gastrinoma,andmedullarycarcinomaofthethyroid

CeliacDisease(sprue)characterizedbyvillusatrophyandcrypthyperplasiadecreasedabsorptionandgreatersecretion;nontropical sprue/glutenenteropathytoxiceffectofglutenonintenstinalmucosa;tropicalsprueinfectiousetiologyandtxbyantibacterialagents

TreatmentofDiarrhea
Increasedintestinalabsorptionstimulatingmucosalabsorptiveprocessesorbyincreasingabsorptivecontacttimebyinhibitingpropulsivemotor contractionsandincreasingsegmentalmotorcontractions. Decreasedintestinalsecretioninhibitingactiveanionsecretionandsecondarywatermovement

IV.

NutrientAbsorption

CarbohydrateAbsorptionintheSmallIntestine
CarbSources Carbscomeinformofstarchsucrose,andlactose Starchmajorstoragepolysaccharideofplantandcomposedofamyloseandamylopectin Carbintake250800g/day5060%ofaveragewesterndiet OtherCarbsenterGItractandareaunavailableforabsorptionincludingelluloseanddietaryfiber;partialabsorptionmayoccurbybacterial fermentationincolonyieldingabsorptableproducts IntraluminalDigestion DigestionbeginswithsalivaryamylaseandisinactivatedbyacidicpHinstomach Nocarbohydrasesingastricjuice Pancreaticamylaseissecretdinpancreaticjuice; Amylosecontains14linkedglucosemolecules~20%ofdietarystarch Amylopectincontains14and16linkedglucose~80%ofdietarystarch Digestionbyamylaseisrapidandhydrolizesthe14linkagesonly Resultingproductsaremaltose,maltotriose,andlimitdextrins(16glucoses) AbsorptioninSmallIntestine Brushborderdigestionbycarbohydrases:maltase,sucrase,lactase,andlimitdextrinase;entryofmonosaccharidesintocellisratelimitingstep Onlymonosaccharidesareabsorbsedbyenterocytes:glucose,galactose,andfructose: FructosemoveintocellalongconcentrationgradientbycarriermediatedfacilitateddiffusionbyGLUT5transporter GlucoseandGlactoseenterviaNa+transportbySGLT1;exitbyfacilitateddiffusionbyGLUT2(Na+independent)andbypassive diffusionthenintocapillariesofvilus; Normallyallcarbsareabsorbedbymidjejunum

ProteinAbsorptionintheSmallIntestine
ProteinSources Exogenousdietaryproteinsarelargestsourceofaa;intakeisabout75100g/day Endogenouslargeamountisderivedbyhydrolyticenzymesandglucoproteinscontainedinsecretions;about3040g/day3050%oftotalprotein IntraluminalDigestion Digestionbeginsinstomachwithactionofpepsinfromchiefcellsinresponsetovagalstimulation; SecretionofproteolyticenzymesisstimulatedbyCCKwhenproteindigestionproductsarepresentintheduodenum;trypsinisactivatedby enterokinaseinthebrushborderswhichthenactivatesalltherestoftheproteases; Productsofexopeptidasesandendopeptidasesare70%peptides(di/tripeptides)and30%freeaminoacids AbsorptioninSmallIntestine Enterocytepeptidasesmoreenterocyticpeptidasesbreakdownproteinsevenfurther; Freeaminoacidsareabsorbedbymanydifferentmechanismsandtransportofaminoacidsistheratelimitingstep Mostproteinisabsorbedinformofdi/tripeptidesviaNa+dependentandindependenttransports;onceinsidemoreICpeptidaseshydrolyzethese peptidesintofurtheraminoacids; AAsandpolypeptiesleavethecellbyfacilitatedorpassivediffusionbythejejunum/ileum

AbsorptionofWaterSolubleVitamins
VitaminB1,6,2,(Folicacid,thiamine,andpyroxidin),riboflavin,nicotinicacidandvitaminCareallabsorbedbyavarietyofmechanismsincluding facilitated,passivediffusion,andcarriermediatedtransport. B12(cobalamin)absorptionrequiresformationofacomplexwithintrinsicfactorproducedbyparietalcellsinthestomach;complexremainsin lumenuntilitbindstoreceptorsonenterocytesintheileum;thenitisactivatelyabsorbedandisboundtotranscobalaminintheblood.

LipidAbsorptionintheSmallIntestine
DietaryLipids Intakevariesfrom12160g/day3040%ofcaloriesinavgwesterndiet Lipidscanbenonpolarwhicharewaterinsolubleorpolarwhichhavebothpolarandnonpolargroupsandsolubilitydependsonratioofgroups StructureFAchainlengthdeterminetheirwatersolubility;dietcontainsmostlylongchainfattyacids;threeformsbasedonpHofsolutionand availabilityofionstoformsalts;insaltformFAcanformmicelles Acylglycerolfatandformedbyattachmentoffattyacidtoglycerol;threefattyacidstoglycerolmakestriglyceride~90%ofdietarylipid Phospholipidsmajorcomponentsofcellmembranes;mostlyderivedfromcellsthataresloughedalongtheintestines Steroidprimarilycholesterol;bileacidsarederivativesofcholesterol IntraluminalDigestion Digestionbeginsinthesalivawithlinguallipase. MechanicalDigestionintheduodenum;fatisemulsifiedintosmalldropletsbybilesalts,lecithinandintestinalcontractions;increasesSAandoil waterinterfact;CCKisreleasedbypresenceoffatinduodenumtoreleasepancreaticsecretions ChemicalDigestion Triglyceridespancreaticcolipasebindstothetriglycerideattheoilwaterinterfacetoallowlipasetoworkwithoutbeinginactivatedby bilesalts;lipasebreaksdowntriglyceridesinto2monoglycerideandfattyacids; PhospholipidshydrolyzedbyphospholiaseA2inthepresenceofCa2+andbilesaltscleavesthefattyacidfromphospholipid; Cholesterolpresentinthedietascholesterolester;secretedinpancreaticjuiceandcleavesthefattyacidfromcholesterolestertoyield freecholesterol AbsorptionofFat SolubilizationofFatemulsifiedproductsformmixedmicelleswithbilesalts;cholesterolandfatsolublevitaminsareinthefatsolubleinterioro themicelle;facilitatemovementoffatsolublesubstancesthroughaqueouschyme. Cellularuptakemicellesmustpastthroughunstirredwaterlayerwhichincludesthemucouscoatandthelipidmembranebarrierthenthelipids canpassivelydiffuseintotheenterocyte;dependsontheconcentrationgradientandsolubilityoflipidproductinthemembrane; Bilesaltsimplemicelleisthenrecycledbackintolumen ConjugatedbilesaltsareabsorbedintheterminalileumbyaNa+dependentactivetransportprocess IntracellularMetabolism Reesterificationafterthelipidproductsentertheenterocytetheyenterthesmoothendoplasmicreticulumwheretheyarereconstituted Chylomicronformationandsecretionreformedlipidscoalesceintochylomicronswhichcontainaprimarycoreoftriglyceridesandcholesterol surroundedbyaphospholipidcoat;transportedoutbyexocytosisthenenterlactealsintothelymphaticcirculation Almostalllipidsareabsorbedbymidjejunumwithmostintheduodenum

AbsorptionofFatsolubleVitamins
FatsolublevitaminsA,D,E,andKareabsorbedinproximalintestinethroughformationofmicelleswithbilesalts

DigestionandAbsorptionofNutrientsintheColon
BacteriaintheColon Thecoloncantabsorbprimarybreakdownofproducts,butmicrobesinthecoloncanfurthermetabolizenutrientsintoproductsthatcanbe absorbed; MIcrofloraofthecoloncontainbothaerobicandanaerobicbacteriaandabigfactorisduetotheslowmotilityofthecolon Nutrientabsorption Proteindigestionisnotamajoroccurrenceinthecolon Carbs(fiber)canbeconvertedintoshortchainfattyacids(SCFA)bybacterialfermentation,whichprovidesamajorsourceofgas;SCFAarethe preferredfuelofcolonocytes;

Carbohydratemalabsorption(lactose)increasesosmoticloadtothecolonandincreasesincidenceofdiarrhea Lipiddigestioncontinuesbybacteriallipaseswhichhydrolyzefattyacidestersintohydroxyfattyacidswhichstimulatefluidsecretion;cholesterol isrelativelyuntouchedinthecolon Bileacidsnotabsorbedintheileumenterthecolonandareextensivelymetabolizedbythebacteria;stimulatefluidsecretion

ColonicGasSources
SwallowedAir CO2liberatedfromreactionofH2andHCO3inthelumen VolatileFattyAcidsprodcedbycolonicbacteria Diffusionofgasfrombloodtolumen Bacteriamakehydrogenfromcarbsdeliveredtothelumen; HydrogenbreathtestcanbeusedtodiagnosecarbmalabsorptionsinceH2entersblodandiseliminatedvialungs MethaneandCO2areproducedbycolonicbacteria;methaneproductionisfamilial,producingfloatingstool Nitrogenmostcommongasinnormalindividuals