Epithelial defects. A variety of epithelial defects have been described in Crohn disease, ulcerative colitis, or both. For example, defects in intestinal epithelial tight junction barrier function occur in patients with Crohn disease and a subset of their healthy first-degree relatives. This barrier dysfunction cosegregates with specific disease-associated NOD2 polymorphisms, and experimental models demonstrate that barrier dysfunction can activate innate and adaptive mucosal immunity and sensitize subjects to disease. Interestingly, the Paneth cell granules, which contain anti-microbial peptides that can affect composition of the luminal microbiota, are abnormal in patients with Crohn disease carrying ATG16L1 mutations, thus providing one potential mechanism in which a defective feedback loop between the epithelium and microbiota could contribute to disease pathogenesis.
Microbiota. The quantity of microbial organisms in the gastrointestinal lumen is enormous, amounting to as many as 1012 organisms/mL of fecal material in the colon (50% of fecal mass). There is significant interindividual variation in the composition of this microbial population, which is modified by diet and disease. Microbial transfer studies are able to promote or reduce disease in animal models of IBD, and clinical trials suggest that probiotic (or beneficial) bacteria or even fecal microbial transplants from healthy individuals may benefit IBD patients.
One model that unifies the roles of intestinal microbiota, epithelial function, and mucosal immunity suggests a cycle by which transepithelial flux of luminal bacterial compo nents activates innate and adaptive immune responses. In a genetically susceptible host, the subsequent release of
TNF and other immune signals directs epithelia to increase tight junction permeability, which further increases the flux of luminal material. These events may establish a self- sufficient to initiate IBD. With this background of pathogenesis we will discuss next the morphologic and clinical features of each of the two forms of IBD.
MORPHOLOGYCrohndisease,alsoknownasregional enteritis, mayoccurinanyareaofthegastrointestinaltractbutthemostcommonsitesinvolvedatpresentationaretheterminal ileum, ileocecal valve, andcecum. Diseaseislimitedtothesmallintestinealoneinabout40%ofcases;thesmallintestineandthecolonbothareinvolvedin30%ofpatients;andtheremainderofcasesarecharacterizedbycolonicinvolvementonly.Infrequently,Crohndiseasemayinvolvetheesophagusorstomach.Thepresenceofmultiple,separate,sharplydelineatedareasofdisease,resultinginskip lesions, ischaracteristicofCrohndiseaseandmayhelpindifferentiationfromulcerativecolitis.Stricturesarecommon(
Fig.15.28A
Theearliestlesion,theaphthous ulcer, mayprogress,andmultiplelesionsoftencoalesceintoelongated,serpentineulcersorientedalongtheaxisofthebowel.Edemaandlossofnormalmucosalfoldsarecommon.Sparingofinterspersedmucosaresultsinacoarselytextured,cobblestone appearanceinwhichdiseasedtissueisdepressedbelowthelevelofnormalmucosa(
Fig.15.28B ).Fissures frequentlydevelopbetweenmucosalfoldsandmayextenddeeplytobecomesitesofperforationorfistulatracts.Theintestinalwallisthickenedasaconsequenceoftrans-muraledema,inflammation,submucosalfibrosis,andhypertrophyofthemuscularispropria,allofwhichcontributetostrictureformation.Incaseswithextensivetransmuraldisease,mesentericfatfrequentlyextendsaroundtheserosalsurface(creeping fat) (
Fig.15.28C