消化道病理二

消化道病理二溃疡性结肠炎（Ulcerativecolitis）克罗思病（Crohn’sdisease）未定型结肠炎（Indeterminatecolitis）IBM一词主要是指两种肠病：克罗思病和溃疡性结肠炎。两者临床病程与病史不同，病变有别，但某些特点相同，而治疗原则不同。

Inflammatoryboweldiseaseisatermthatdescribestwodiseases:Crohndiseaseandulcerativecolitis.Althoughthesetwodisordershavedifferentclinicalcoursesaswellasnaturalhistoriesandareusuallyclearlydistinguishable,theyhavecertaincommonfeatures.IBD的类型无特异性实验室检测指标（Nospecificlaboratorytests）抗中性粒细胞胞质抗体

pANCA(anti-neutrophilcytoplasmicantibody)60-75%的溃疡性结肠炎病例（Ulcerativecolitis:60-75%）10-40%的克罗思病病例（Crohn’sdisease:10-40%）抗酿酒酵母菌抗体

ASCA(anti-Saccharomycescerevisiaeantibody)40-80%的溃疡性结肠炎病例（Crohn’sdisease:40-80%）

<10%的克罗思病病例（Ulcerativecolitis:<10%）基因检测：NOD2和其他的IBD基因

（GenetictestingforNOD2andotherIBDgenes）

IBD的实验室检测克罗恩病

（CrohnDisease）

克罗恩病（CrohnDisease）

肠炎特点（FeaturesofInflammationoftheIntestine）

慢性，节段性，透壁性（Chronic,Segmental,Transmural）病变以小肠远端为主，右半结肠可受累，可有消化道甚至肠外组织受累

（Crohndiseaseoccursprincipallyinthedistalsmallintestinebutmayinvolveanypartofthedigestivetractandevenextraintestinaltissues.Thecolon,particularlytherightcolon,maybeaffected.）2023/12/29克罗恩病的流行病学（Epidemiology）全球发生克罗思病，每年发病率为0.5-5人/每10万人群。过去30年来，来自各国的报道表明，全球的克罗思发病率急剧增加。

（Crohndiseaseoccursworldwide,withanannualincidenceof0.5to5per100,000.Reportsfromvariouscountriesindicatethattheincidencehasincreaseddramaticallyoverthepast30years.）欧洲的该病病例最常见于青少年或年轻成人,犹太人群呈高发病率，女性较男性稍微多见(1.6:1).

ThediseaseusuallyappearsinadolescentsoryoungadultsandismostcommonamongpersonsofEuropeanorigin,withaconsiderablyhigherfrequencyintheJewishpopulation.Thereisaslightfemalepredominance(1.6:1).2023/12/29发病机制（Pathogenesis）家族性遗传性体质

ConcordanceratesintwinpairsandsiblingsstronglyimplicateageneticpredispositiontoCrohndisease.AfamilyhistoryofinflammatoryboweldiseaseismorecommonforCrohndiseasethanforulcerativecolitis.AputativesusceptibilitylocusforCrohndiseasehasbeenassignedtothecentromericregionofchromosome16whereitisassociatedwiththeNOD2/CARD15locus,whichcodesforanintracellularreceptorforbacterialproductsinvolvedininnateimmunity.自身免疫机制

ThepossibilitythatCrohndiseasereflectsimmunologicallymediateddamage

totheintestineissuggestedby(1)thechronicandrecurrentnature（慢性反复发作）

oftheinflammationand(2)itsassociationwithsystemicmanifestations（全身损害）

thataresuggestiveofautoimmunedisease.Mostrecentimmunologicstudiesfocusonthepossibleroleofcell-mediatedcytotoxicity.2023/12/29肠道粪便流的作用ThefecalstreamappearstobeofprimeimportanceinthepathogenesisofCrohndisease,asevidencedby：(1)thebeneficialeffectsofsurgicalbypass（肠旁路吻合的好处）(2)thepatternofpreanastomoticrecurrenceinpatientswithside-to-endanastomoticsites（侧-端吻合处前段复发）,and(3)thefrequencyofearlyinflammatorylesions(aphthoiderosions)intheepitheliuminassociationwithmucosallymphoidtissue（淋巴组织增生之上皮处早期炎症-口疮样糜烂）.2023/12/29病理变化（Pathology）

克罗思病有两大病变特征，以此与其他的炎症性肠病相鉴别：

TwomajorcharacteristicsofCrohndiseasedifferentiateitfromotherGIinflammatorydiseases.

第一，严重通常累及肠壁全层，故称之为透壁性炎症。

First,theinflammationusuallyinvolvesalllayersofthebowelwallandis,therefore,referredtoastransmuralinflammatorydisease.第二，肠壁病变是间断性的，即节段性肠炎病变，间有未受累及的正常肠组织

Second,theinvolvementoftheintestineisdiscontinuous;thatis,segmentsofinflamedtissueareseparatedbyapparentlynormalintestine.2023/12/29克罗恩病病变分布的四大部位特征回盲部病变为主，占50%

mainlytheileumandcecuminabout50%ofcases仅有小肠病变，占15%

onlythesmallintestinein15%仅有大肠病变，占20%

onlythecolonin20%肛门直肠区病变为主，占15%

女性肛门直肠区克罗恩病可蔓延到外阴部

mainlytheanorectalregionin15%.InwomenwithanorectalCrohndisease,theinflammationmayspreadtoinvolvetheexternalgenitalia.2023/12/29大体观(Grossly)肠壁与邻近肠系膜增厚，水肿，肠系膜脂肪环绕肠周（爬行脂肪）

Thebowelandadjacentmesenteryarethickenedaswellasedematous,andmesentericfatoftenwrapsaroundthebowel(Creepingfat).肠系膜淋巴结常常肿大，变硬，相互融合

Mesentericlymphnodesarefrequentlyenlarged,firm,andmattedtogether.

肠腔狭窄（水肿与纤维化共同作用所致），可见鹅卵石状外观（因结节状肿胀、肠壁纤维化和粘膜溃疡所致）

Theintestinallumenisnarrowedbyacombinationofedemaandfibrosis.Nodularswelling,fibrosis,andmucosalulcerationleadtoacobblestoneappearance.

溃疡特点：早期的溃疡呈口疮状或葡行状；晚期的溃疡变深呈线状裂缝或裂纹状

Inearlycases,ulcershaveeitheranaphthousoraserpiginousappearance;later,theybecomedeeperandappearaslinearcleftsorfissures(seeFig.13-23B).2023/12/29图片A.末端回肠远端肠壁明显增厚，伴有回盲瓣变形。可见一纵向溃疡(箭头所示)图片B.该回肠节段另一纵向溃疡。受损粘膜水肿，形成圆形/卵圆形结节状隆起，使病变肠段粘膜呈鹅卵石样外观。右下侧局部粘膜部分未受累2023/12/29

克罗恩病肠切除标本大体观大体切面观Thecutsurfaceofthebowelwallshowsthetransmural（透壁性）natureofthedisease,withthickening（增厚）,edema（水肿）,andfibrosis（纤维化）ofalllayers.Involvedloopsofbowelareoftenadherent（粘连）,andfistulas（瘘管）betweensuchsegmentsarefrequent.Thesefistulasmayalsopenetratefromthebowelintootherorgans（肠壁瘘管穿入其它器官）,includingthebladder,uterus,vagina,andskin.Lesionsinthedistalrectumandanusmaycreateperianalfistulas（肛旁瘘）,awell-knownpresentingfeature.2023/12/29Microscopically,Crohndiseaseappearsasachronicinflammatoryprocess.Duringearlyphasesofthedisease,theinflammationmaybeconfinedto（局限于）themucosaandsubmucosa.Small,superficialmucosalulcerations(aphthousulcers口疮样溃疡)areseen.Later,long,deep,fissure-like（裂隙状）ulcersareseen,andvascularhyalinizationandfibrosisbecomeapparent.ThemicroscopichallmarkofCrohndiseaseistransmural,nodular,lymphoidaggregates(Fig.13-24).Discrete（散在的）,noncaseating（非干酪样）granulomas（肉芽肿）,mostlyinthesubmucosa,maybepresent.AlthoughthepresenceofgranulomasisstrongevidenceinfavorofCrohndisease,lessthanhalfofthecasesshowtheselesions.ThepathologicfeaturesofCrohndiseasearesummarizedinFigure13-25.2023/12/29正常的结肠粘膜组织结构Figure13-24.克罗恩病.图片A显示溃疡至粘膜下层；淋巴组织聚集在粘膜下、邻近肌层和浆膜下。图片B显示粘膜活检，可见小灶上皮样肉芽肿位于两个无损的腺隐窝之间。

A.ThecoloninvolvedwithCrohndiseaseshowsanareaofmucosalulceration,anexpandedsubmucosawithlymphoidaggregates,andnumerouslymphoidaggregatesinthesubserosaltissuesimmediatelyadjacenttothemuscularisexterna.B.ThismucosalbiopsyinCrohndiseaseshowsasmallepithelioidgranuloma(arrows)betweentwointactcrypts.2023/12/29克罗恩病的肉芽肿病变克罗恩病肉芽肿的高倍镜下观大肠腺上皮隐窝结构变形克罗恩病回肠炎下图见裂缝状溃疡逆流性回肠炎克罗恩病肠道活检H-E染色切片组织学观察箭头所示克罗恩病的透壁性炎症临床特点(ClinicalFeatures)克罗恩病的临床表现与病史各自不同，与发病部位相关TheclinicalmanifestationsandnaturalhistoryofCrohndiseasearehighlyvariableandrelatetotheanatomicalsitesinvolvedbythedisease.

最常见症状：75%病人腹痛腹泻；50%病人回归热Themostfrequentsymptomsareabdominalpainanddiarrhea,whichareseeninmorethan75%ofpatients,andrecurrentfever,evidentin50%.

吸收不良和营养不良；腹泻和肠出血；以直肠肛门病变为主的可反复发生肛瘘

Whenthesmallintestineisdiffuselyinvolved,malabsorptionandmalnutritionmaybemajorfeatures.Crohndiseaseofthecolonleadstodiarrheaandsometimescolonicbleeding.Inafewpatients,themajorsiteofinvolvementistheanorectalregion,andrecurrentanorectalfistulasmaybethepresentingsign.2023/12/29克罗恩病的继发病变肠道阻塞、瘘管和肠穿孔IntestinalobstructionandfistulasarethemostcommonintestinalcomplicationsofCrohndisease.Occasionally,freeperforationoftheboweloccurs.发生肠癌

SmallbowelcancerisatleastthreefoldmorecommoninpatientswithCrohndisease,andthediseasealsopredisposestocolorectalcancer.NocureforCrohndiseaseisavailable.Severalmedicationssuppresstheinflammatoryreaction,includingcorticosteroids,sulfasalazine,metronidazole,6-mercaptopurine,cyclosporine,andanti-TNFantibodies.Surgicalresectionofobstructedareasorofseverelyinvolvedportionsofintestineanddrainageofabscessescausedbyfistulasareoftenrequired.2023/12/29克罗恩病小肠节段性病变特征模式图2023/12/29溃疡性结肠炎

（UlcerativeColitis

）

溃疡性结肠炎（UlcerativeColitis）是结直肠发生的慢性浅表性炎症UlcerativeColitisisaChronicSuperficialInflammationoftheColonandRectum临床表现慢性腹泻，直肠出血。是有加重和缓解，可伴有局部和全身并发症Ulcerativecolitisischaracterizedbychronicdiarrheaandrectalbleeding,withapatternofexacerbationsandremissionsandwiththepossibilityofseriouslocalandsystemiccomplications.2023/12/29流行病学（Epidemiology）InEuropeandNorthAmerica,theincidenceofulcerativecolitisis4to7per100,000population,anditsprevalenceis40to80per100,000.Itusuallybeginsinearlyadultlife,withapeakincidenceinthethirddecade.However,italsooccursinchildhoodandoldage.IntheUnitedStates,whitesareaffectedmorecommonlythanblacks.2023/12/29发病机制（Pathogenesis）原因不清，可能与遗传相关Thecauseofulcerativecolitisisunknown.Insomefamiliesasmanyassixpatientswiththisdiseasehavebeendescribed,andconcordancehasbeenreportedinmonozygotictwins.However,availablefamilystudiesdonotsuggestanydistinctmodeofgenetictransmission.自身免疫病机制

Thepossibilitythatanabnormalimmuneresponsemaybeinvolvedhasbeenstudiedextensively.Thereisabundantlymphoidtissuethroughoutthecolon,andulcerativecolitismayoccurwithautoimmune-likeconditions,suchasuveitis,erythemanodosum,andvasculitis.Increasedcirculatingantibodiesagainstantigensincolonicepithelialcellsandagainstcross-reactingantigensinenterobacteriamayoccur.Antineutrophilcytoplasmicantibodiesarefoundin80%ofpatientswithulcerativecolitis.However,theseabnormalitiesareneitheruniqueforulcerativecolitis,noraretheyaprerequisiteforthedevelopmentofthedisease.2023/12/29病理变化（Pathology）Ulcerativecolitisisadiffusedisease.Itusuallyextendsfromthemostdistalpartoftherectum（远端直肠）foravariabledistanceproximally(Fig.13-26).Sparingoftherectumorinvolvementoftherightsideofthecolonaloneisrareandsuggeststhepossibilityofanotherdisorder,suchasCrohndisease.Inflammationinulcerativecolitisisgenerallylimitedtothecolonandrectum.Itrarelyinvolvesthesmallintestine,stomach,oresophagus.Ulcerativecolitisisessentiallyamucosaldisease.Deeperlayersareuncommonlyinvolved,mainlyinfulminantcasesandusuallyinassociationwithtoxicmegacolon.2023/12/29三大主要病变Threemajorpathologicfeaturescharacterizeulcerativecolitisandhelptodifferentiateitfromotherinflammatoryconditions:Figure13-26.Ulcerativecolitis.Prominenterythemaandulcerationofthecolonbeginintheascendingcolonandaremostsevereintherectosigmoidarea.2023/12/29Thefollowingmorphologicsequencemaydeveloprapidlyoroveracourseofyears.EARLYCOLITIS:Earlyintheevolutionofthedisease,themucosalsurfaceisraw,red,andgranular.Itisfrequentlycoveredwithayellowishexudateandbleedseasily.Latersmall,superficialerosionsorulcersmayappear.Theseoccasionallycoalescetoformirregular,shallow,ulceratedareasthatappeartosurroundislandsofintactmucosa.Themicroscopicfeaturesofearlyulcerativecolitisinclude(1)mucosalcongestion,edema,andmicroscopichemorrhages;(2)adiffusechronicinflammatoryinfiltrateinthelaminapropria;and(3)damageanddistortionofthecolorectalcrypts,whichareoftensurroundedandinfiltratedbyneutrophils.Suppurativenecrosisofthecryptepitheliumgivesrisetothecharacteristiccryptabscess,whichappearsasadilatedcryptfilledwithneutrophils(Fig.13-27).2023/12/29Figure13-27.Ulcerativecolitis.A.Afull-thicknesssectionofcolonresectedforulcerativecolitisshowsinflammationaffectingthemucosawithsparingofthesubmucosaandmuscularispropria.B.Sectionsofamucosalbiopsyfromapatientwithactiveulcerativecolitisshowexpansionofthelaminapropriaandseveralcryptabscesses(arrows).C.Chroniculcerativecolitisshowssignificantcryptdistortionandatrophy.2023/12/29PROGRESSIVECOLITIS:Asthediseasecontinues,mucosalfoldsarelost.Lateralextensionandcoalescenceofcryptabscessescanunderminethemucosa,leavingareasofulcerationadjacenttohangingfragmentsofmucosa.Suchmucosalexcrescencesaretermedinflammatorypolyps.Granulationtissuedevelopsindenudedareas.Importantly,thestricturescharacteristicofCrohndiseaseareabsent.Microscopically,colorectalcryptsmayappeartortuous,branched,andshortenedinthelatestages,andthemucosamaybediffuselyatrophic.2023/12/29ADVANCEDCOLITIS:Inlong-standingcases,thelargebowelisoftenshortened,especiallyintheleftside.Mucosalfoldsareindistinctandarereplacedbyagranularorsmoothmucosalpattern.Microscopically,advancedulcerativecolitisischaracterizedbymucosalatrophyandachronicinflammatoryinfiltrateinthemucosaandsuperficialsubmucosa.Panethmetaplasiaiscommon.2023/12/29ClinicalFeaturesTheclinicalcourseandmanifestationsareveryvariable.Mostpatients(70%)haveintermittentattacks,withpartialorcompleteremissionbetweenattacks.Asmallnumber(<10%)haveaverylongremission(severalyears)aftertheirfirstattack.Theremaining20%havecontinuoussymptomswithoutremission.2023/12/29MILDCOLITIS:Halfofpatientswithulcerativecolitishavemilddisease.Theirmajorsymptomisrectalbleeding,sometimesaccompaniedbytenesmus(rectalpressureanddiscomfort).Thediseaseinthesepatientsisusuallylimitedtotherectumbutmayextendtothedistalsigmoidcolon.Extraintestinalcomplicationsareuncommon,andinmostpatientsinthiscategory,diseaseremainsmildthroughouttheirlives.2023/12/29MODERATECOLITIS:About40%ofpatientshavemoderateulcerativecolitis.Theyusuallyhaverecurrentepisodesofloosebloodystools,crampyabdominalpain,andfrequentlylow-gradefever,lastingdaysorweeks.Moderateanemiaisacommonresultofchronicfecalbloodloss.2023/12/29SEVERECOLITIS:About10%ofpatientshavesevereorfulminantulcerativecolitis,oftenduringaflareofactivity.Theymayhavemorethan6andsometimesmorethan20bloodybowelmovementsdaily,oftenwithfeverandothersystemicmanifestations.Bloodandfluidlossrapidlyleadstoanemia,dehydration,andelectrolytedepletion.Massivehemorrhagemaybelife-threatening.Aparticularlydangerouscomplicationistoxicmegacolon,whichischaracterizedbyextremedilationofthecolonandanassociatedhighriskforperforation.Fulminantulcerativecolitisisamedicalemergencyrequiringimmediate,intensivemedicaltherapy,and,insomecases,promptcolectomy.About15%ofpatientswithfulminantulcerativecolitisdieofthedisease.2023/12/29ThedistinctionbetweenulcerativecolitisandCrohncolitisisbasedondifferentanatomicallocalizationandhistopathology(Table13-1).Themedicaltreatmentofulcerativecolitisdependsonthesitesinvolvedandtheseverityoftheinflammation.The5-aminosalicylate鈥揵asedcompoundsarethemainstaysoftreatmentforpatientswithmild-to-moderateulcerativecolitis.Corticosteroidsandimmunosuppressiveandimmunoregulatoryagents(azathioprineormercaptopurine)areusedinpatientswhohavesevereandrefractorydisease.2023/12/29ExtraintestinalManifestationsArthritisisseenin25%ofpatientswithulcerativecolitis.Eyeinflammation(mostlyuveitis)andskinlesionsdevelopinabout10%.Themostcommoncutaneouslesionsareerythemanodosumandpyodermagangrenosum;thelatterisaserious,noninfectivedisordercharacterizedbydeep,purulent,necroticulcersintheskin.Liverdiseaseoccursinabout4%ofpatients,mostcommonlyprimarysclerosingcholangitis.Thromboembolicphenomena,usuallydeepveinthrombosesofthelowerextremities,occurin6%ofulcerativecolitispatients.2023/12/29UlcerativeColitisandColorectalCancerPeoplewithlong-standingulcerativecolitishaveahigherriskofcolorectalcancerthanthegeneralpopulation.Colorectalepithelialdysplasiaisaneoplasticepithelialproliferationandprecursortocolorectalcarcinomainpatientswithlong-termulcerativecolitis.High-gradeepithelialdysplasiareflectsasignificantriskforthedevelopmentofcolorectalcancer,andwhenidentifiedinabiopsy,itisastrongindicationforcolectomy.2023/12/29TABLE13-1ComparisonofthePathologicFeaturesintheColonofCrohnDiseaseandUlcerativeColitis2023/12/29LesionCrohnDiseaseUlcerativeColitisMacroscopIcThickenedbowelwallTypicalUncommonLuminalnarrowingTypicalUncommon透壁性lesionsCommonAbsentRightcolonpredominanceTypicalAbsentFissuresandfistulasCommonAbsentCircumscribedulcersCommonAbsentConfluentlinearulcersCommonAbsentPseudopolypsAbsentCommonMICROSCOPIcTransmuralinflammationTypicalUncommonSubmucosalfibrosisTypicalAbsentFissuresTypicalRareGranulomasCommonAbsentCryptabscessesUncommonTypicalSUMMARYCrohndiseaseandulcerativecolitisareidiopathicinflammatoryboweldiseasesbelievedtoresultfromabnormallocalimmuneresponsesagainstunknownmicrobesand/orselfantigensintheCrohndiseaseAssociatedwithHLA-DR7and-DQ4alleles,andwithmutationsintheNOD2gene,whichencodesanintracellularsensorofmicrobesResultsfromachronicTcell-mediatedinflammatoryreactioninvolvingIFN-γ-producingTH1cellsand,perhaps,IL-17-producingTH17cellsManifestedbychronicinflammationwithgranulomas,ulcers,andstricturescausedbyfibrosis,involvingtheterminalile