REVIEW

Upper gastrointestinal tract Crohn's disease

H UG H) FREEMAN. MD

NY SITE WITHIN THI:: GASTROINTEST ABSTRACT: Crohn's disease may involve any site within the gastrointestinal inal tract may involved in Crohn's tract. Usually pathology is present in the ileum and/or colon, but atypical presen­ A be tations may occur with apparently 'isolated' involvement of the oropharynx, esoph­ disease (I) lt is well recognized that agus or gastroduodenum. lf changes typical of Crohn 's disease are detected in the Ueal and/or colonic involvement arc most upper gastrointestinal tract, then a careful assessment is required involving often present, but occasionally 'isolated' radiographic, endoscopic and histologic studies to determine if pathology is present disease locali zed to o ne or more sites in in more distal intestine. In addition, microbiologic studies may be important to the upper gastrointestinal tract occurs. exclude infectious causes, especially of granulomas. If these studies are negative, Indeed , if involvement with Crohn'sd1s­ prolonge; follow-up may be required to establish a diagnosis of Crohn's disease. ease is defined by the presence of subtle Although upper gastrointestinal involvement is increasingly recognized as a sig­ endoscopic changes including aph thoid nificant cause of morbidity in Crohn's disease, the treatment options arc limited, ulcera tions or histologic fe atures alone, largely anecdotal and need to be the subject of detailed cpidemiologic investiga­ rhe stomach and duodenum appear to tion and clinical trials. Can J Gastroenterol 1990;4(1):26-32 be relati vely common sites of Crohn's Key Words: Crohn 's disease, Inflammatory bowel disease , Gastrocolic fiscula . Gran­ disease. C hanges in the esophagus have ulomacous gastritis, Ycrsinia entcrocolitica also been recorded but appear to be less Maladie de Crohn des voies digestives superieures frequen t. lf'isolated ' granulomatous dis­ ease is documented , however, carefu l ex· RESUME: La maladie de Crohn peut etre localisee a un niveau quelconque du clusion of other ca uses of granuloma is tube digestif. Habituellement, elle affecte l'ileon et/ou le colon mais elle peut se required. Generally, this should include manifester de far,:on atypique ct attei nd re l'oropharynx, l'esophage ou le gastro­ an evaluation of the distal small and large duodenum. Si certains changements attribuables ala maladie de Crohn sont de­ bowel to determine if the more typical celes clans la voie digestive superieure, ii faut alors proceder a une evaluation radiographic, endoscopic or histologic soigneuse comprenant des exam ens radiographiques. endoscopiques et histologi­ features of C rohn 's disease are present. ques destines a determiner si la maladie s'est propagee a d'autres segments de l'intestin. De plus, ii peut etre important de proceder ades cxamens microbiolo­ giques afin d'exclure !es origines infecrieuscs - dans le cas des granulomes sur­ GASTRODUODENAL DISEASE tout. Si les resultats sont ncgatifs. un suivi prolonge peut etre necessaire avant Frequency: Some of the earliest re· que le diagnostic definitif de maladie de Crohn ne soit pose. Bien que la partici­ ports recognizing gastric involve ment in pation de la voie digestive superieure soit de plus en plus reconnue com me une Croh n's disease were recorded by Ross cause importante de morbidite dans la maladie de Crohn. les options de traite­ (2) in J949 andComfort etal(3)in 1950. ment sont limitees et largement anecdotiques. Elles meriteraient de faire l'objet Since then , well over 100 patients have d'investigations epidemiologiques detaillees et d 'essais cliniques. heen reported with granulomatous in- ammatory disease of the stomach and Deparrment of Medic111e (Gastroenterology), University Hospiwl; and University of British duodenum attributed to C rohn's disease. Columbia. Vancouver, British Col1m1bia As the majority of these reports have Corres/Jondence and reprints. Dr Hugh Freeman, Head, Gas rroemerology, ACU F-137, University Hospiwl. Univers icy oj Bri rish Colambia, 221I Wesbrook Mall, Vancouver. Br1tish focused largely on clinically significant Columbia V6T IW5. Telephone/604) 228-7216 or 7235 involvement, estimated to be approx1· Received for puhlicanon June I9. J989. Accepted Se/ncmber I9. 1989 rnately 2 to 4% of all patients (4 ). the true

26 CAN J GASTROENTEROL VOL 4 No I JANUARY/FEBRUARY 1990 Crohn's disease

frequency is likely to be much higher. tolog1cal features of C ro hn's disease. In entity may represent an early stage of Indeed. initial reports suggested that the addition to blood loss, however. anemia the disease. prevalence of patients with documented may result from deficits of iron or folic ln patients with duodenal disease, a Crohn's disease e lsewhere in the gastro­ acid due in part to reduced absorption concomitant inflammatory change in the intestinal tract was no more than 7°{, from a diseased proximal small intestine. pancreas or biliary tract may be present. (5-7). Subsequent studies. however, in­ 'Isolated' gastric disease: In some In this setting, bi liary tract stones or dicate that disease was r resent in the patients, gastric involvement alone may sludge, as well as the reflux of duodenal upper gastrointestina l tract in over 20% occur ( 13.18). In these patients, pain may content into the pancreatic duct through (8.9). This reflects, in part, an increased be a prominent sy mptom and although an incompetent ampulla. have been de­ appreciation in recent years for the wide­ no obstructio n is evident, abnormal gas­ scribed (29- 31 ). ln others, drug induced spread, often segmental or focal nature tric emptying may still occur. Diagnosis disease o f the pancreas has been re­ of this inflammatory p rocess within the may be suggested by nuclear scans or by ported, especially with sulfasalazine (32). gastrointestinal tract. Moreover, the com­ barium studies showing impaired e mp­ metronidazole ( 33) and immunosup­ bined use of upper e ndoscop y and tying of contrast; in the most extre me pressive agents. including azathioprine mucosa! biopsy has increased the incidence situations, a poorly distensible gastric an­ and 6-mercaptopurine (34-36). Alcohol of recognition, even if the disease is clin­ trum. sometimes with aphthoid ulcer­ associated injury can also occur in these ically or radiographically 'silent' at this site. ation and 'cobblestoning' of antral folds patients. More recently. direct ampullary Clinical features: In ma ny patients, with fissuring, ulceration and pyloric de­ involvement with stenosis as well as com­ symptoms relating to the upper gastro­ fo rmity may be present. In one report. mon bile duct obstruction have been re­ intestinal tract may be limited or fre­ the barium radiographic 'ram's horn' sign corded (37). ln addition, duodenal bezoar quently overshadowed hy diarrhea and was described ( 19). In these patie nts, formation (38). and fistulous communi­ other symptoms associated with small or Crohn 's disease may later become evi­ cati on with the pancreatic duct have large intestinal disease. Even significant dent in the more distal small and la rge been described ( 39). symptoms relating to resistant ulceration intestine. Endoscopic features: Endoscopy may and progessive gastroduodenal stenosis 'Isolated' duodenal disease: Isolated in­ permit a better appreciation o f the may go unrecognized until later in the volvement of the proximal small intes­ cha nges associated with Crohn's disease clinical course. ln this setting, marked tine including the duodenum may also in the upper gastrointestinal tract, even nutritional disturbance and weight lo:,s occur (20-24). Most often evidence of ifir is apparently asymptomatic (8,40-45). are cor.,mon. in part reflecting the pro­ such involvement is limited to focal in­ Gastric and duodenal ulceration, espe­ gressive impairment of food intake and flammatory changes or isolated muco­ ciall y linear or serpiginous, may be ob­ impaired gastric emptying of nutrients sa! granulomas, with multinucleated served. The antrum may be poorly dis­ into the small intestine. In some patients, giant cells or loose aggregates and clus­ tensible with ai r insufflation, and rigid the clinical features of anorexia nervosa ters of cpithe lioid cells. In othe rs. more pyloric or pyloroduodenal stenosis may may be present ( 10.11 ). Symptoms re­ severe changes may be present with mul­ prohibit passage of even 'pediatric­ lated to gastric outlet obstruction such tiple and diffuse ste notic small bowel calibre' endoscopes. Macroscopic changes as nausea and vomiting may result. Be­ segments. Such patients are prone to may also include a minimal colour alter­ cause of the cicatrizing nature of this in­ episodes of bowel obstruction, generalized ation, either patchy or diffuse. focal white flammatory process in the antral and py­ malnutrition and numerous specific nodules, a ph thoid u Ice ration or erosion loric region, the proximal stomach may nutrient deficiencies. The frequency of with exudate and apparent mucosa] 'cob­ appear dila ted with retained food more clinically significant, extensive small blestoning'. Strictures and fistulae from debris and sometimes bezoar formation. bowel disease is not known. In one early the stomach or duode num into nearby Hemorrhage. especiall y from deep study (25). based largely on contrast intestinal loops or the pancreatobiliary ulceration. has been possibly incorrectly radiographic examinations. 18 of 330 tract may be appreciated. More often, considered an uncommon presentation patie nts with C rohn 's disease seen from with the development of fi stulae, a co­ for most granulomatous gastric disorders 1944 to 1970 were described as having existent inflammatory focus is present 112); in part, this idea may reflect a ten­ more than diffuse jejunaI involvement. in an adjacent loop o f small or large dency to attribute the cause of ulceration The early lite rature on Crohn's disease bowel - in this setting, the fistula is to 'acid peptic' disease or commonly pre­ (26-28) also describes the laparotomy ap­ usually considered 'secondary' to the in­ scribed analgesics used to m a n age pearances of the small intestine in rare testinal disease (46-54). Often, upper abdominal pain or arthropathy. In addi­ patients characterized by diffuse and endoscopy is limited in its ability to deter­ tion, endoscopic biopsy. especially in this multiple miliary-like granulomatous mine the fistula opening which usually setting, is commonly not done since pa­ serosal lesions; the proximal small bowel appears only as a small, sometimes ery­ tients are usually young so that distinc­ was also involved. In these patients, thematous, raised dimple with exudate tion from neoplastic disease is rarely microbiologic studies, sp ecifi cally for on a raised cluster of gastric folds (55). difficult. If ulcers or erosions are present, Mycobacteriam tuberculosis were neg­ The most common site for a fi stula rec­ however, endoscopic biopsy may reveal ative. This e ntity was termed 'miliary ognized at endoscopy is the greater cur­ granulomas and other more typical his- Crohn 's disease'; it was suggested that this vature of the stomach . usually from the

CAN J GASTROENTEROL VOL 4 No I JANUARY/FEBRUARY 1990 27 FREEMAN

splenic flexure of the colon. ln patients ulomas, exclusion of other causes is war­ of the lymphomatous infiltrates in some with a prior ileocolonic resection. how­ ran ted, particula rly for infectious d is­ patients (69-72). ever. fistulous commu nication berween orders, as their detection may alter ther­ the anastomosis and the descending duo­ apy (6l). In the absence of granulomas. OROPHARYNGEAL AND denum may be seen. Routine bari um Crohn's disease may still be present, es­ ESOPHAGEAL DISEASE or gascrograffin contrast studies remain pecially if a constellation of acute, par­ Crohn 's disease occasionally involves the most useful for diagnosis. although ticularly focal , neutrophuic inflammatory th e mucous membranes of the oro­ contrast introduced d irectly through an changes or crypt abscesses are present pharynx and esophagus. Rarely, the re· endoscopic catheter may also be used. (45) . In occasional patients, small bowel spiratory tract may be involved, distinct Altho ugh a gastrocolic fistula is most biopsies may reveal changes more typi­ from sarcoidosis or infectious disorders common (49-53), other causes of fistula cal of celiac sprue with mucosa! villus such as tuberculosis (58-60). Granuloma­ should also be considered by the endo­ atrophy and crypt hyperplasia (45). These tous inflammation of the mino r salivary scopist in patients with Crohn 's disease, mucosa! biopsy changes may be patchy gland ducts may also occur, causing sub­ including carcinoma of the colon and or d iffuse and variable in the degree of lingual cystic lesions due to d uct rupture stomach as well as lymphoma (56). severity ranging from mild to severe (64). and mucocele formation (73). Usually, Histologic features: Biopsies from nor­ Variable changes may be appreciated involvement of the oropharynx or esoph mal appearing or grossly abnormal gas­ only if multiple small bowel si tes are agus occurs in conjunction with evidence tric mucosa often reveal nonspecific in­ b iopsied . A number of reports have re­ of disease elsewhere, particularly ilcoco· flammatory changes; focal neucrophilic corded the coexistence of celiac sprue Ionic or perianal disease. Often the symp· infiltrates and mulcinucleated giant cells and inflammatory bowel disease in the toms are minimal but some patients may or cpithclioid cell clusters may also be same patients (65); some likely represent complain of painful oral ulce rs, or fre­ seen, and may be more suggestive of pos­ Crohn's disease alone. Differentiation of quently dysphagia or odynophagia. Some­ sible Croh n's disease. The detection of Crohn 's from celiac sprue may be espe­ times these sy mptoms predominate over granulomas is not specific for Crohn's cially difficult in some patients, particu­ bowel symptoms and result in reduced disease, especially if disease is not ap­ larly if C rohn's disease is not readily evi­ food in take. malnutrition and weight loss. parent elsewhere in the intestinal tract. dent in the more distal small or large O ral lesions in C rohn's disease were However, their initial detection in a pa­ bowel; moreover, disorders characterized first reported in 1969 (74). with isolated tient not known co have Crohn 's disease by spontaneous remissions may be dif­ disease of the mouth in 1972 (75). ln the should lea I to endoscopic and radio­ ficult to distinguish even with clinical im­ oropharynx, superficial o r epithe lial graphic assessments of the small and provement on a gluten-free diet. While ulceration is relatively frequent (at least large bowel. H istological distinction of there arc other causes of a 'fl at' small in­ 10%) compared to th e less common the granulomara from other en ti ties, in­ testinal biopsy (64), the acute nature of changes of painful swelling and ulcer­ cluding sarcoidosis, is often not possible the inflammatory process with polymor­ ation of the buccal mucosa, as well as wi th 'isolated ' gastric involvemen t, and phonuclear leukocytes and crypt absces­ the e rythematous gingival hyperplasia diagnosis may be established only after ses may favour a diagnosis of C rohn's associated with histologically docu­ fu rther investigations including pulmo­ disease (4 5). In addition, other entities mented granulomatous inflammatory nary assessment, liver and possibly lymph should be considered if an acute inflam­ disease (less than l %). Other described node biopsy (57-60). In addition, ocher matory process is present withoutgran­ changes include angular chei li ci s, muco­ entities should be excluded in the pres­ ulomas, including Zollinger-Ellison synd­ sa! tags or cobblestoning of the oral mu· ence of isolated' gastric disease. such as rome (66) and so-called 'benign non­ cosa and hyperplastic gingival lesions foreign bodies (eg, suture-associa ted), tu­ granulomatous jejunitis', an entity also (76-79). Finally, the changes associated berculosis, hiscoplasmosis and syphilitic associated with celiac sprue (67). Infec­ with nu trie nt deficiency and the effects gastric involvement as well as ocher in­ tious agents, especia lly if they are com­ of medications, including the Stevens· fectious causes (59-61). Distinction from mon in a specific geographic area, deserve Johnson sy ndro me. may occur. gastric neoplastic disease, although it is careful exclusion. ln the authors' insti­ ln some patients, the pathology may not apparently increased in Crohn's dis­ tution , for example, a commonly recog­ be limited to this si te or be the initial ease, is important. ln the pediatric pa­ nized agent in patients with gastrointes­ clinical manifestation years before the tient, chro nic gra nulomarous disease tinal disease is Yersinia enterocolitica; in disease is detected elsewhere in the gas· may be a special consideration, especially the authors' studies, endoscopic and his­ troi ntestinal tract (80,81). In such pa­ if gastric outlet obstruction is present tologic changes in the upper gastroin­ tients, conside ration should be given to (62 ). The sy ndrome of necrotizing gran­ testinal tract have been frequent (68). such entities as Behcet's sy ndrome if other ulomatous gastritis seems sufficiently dis­ Finally, the possibility of lymphoma in clinical features of this d isorder are pre­ tinct from the pathological changes in the proximal small intestine must be con­ sent, such as genital ulceration. In addi­ Crohn 's disease such that differentiation sidered ; this distinction may be especially tion , microbiological causes oforal ulcer· is not usually difficult (63). If endoscopic d ifficult because of the frequent pres­ ation require exclusion. notably Y encero­ or suction biopsies of the d uodenum or ence of ulcerated and inflamed small in­ colitica, an infectious agent that has been proximal jejunum reveal 'isola ted' gran- testine in lymphoma and the focal nature associated with a clinical sy ndrome of

28 CAN J GASTROENTEROL VOL 4 No I JANUARY/FEBRUARY 1990 Crohn's disease

ilcocolitis similar to Crohn 's disease (68). history of tuberculostatic or antiherpetic port, omeprazolc appeared to provide The pathogenesis of the oral lesions in therapy was frequent. symptomatic benefit in certain patients Crohn's disease remains unknown. Re­ Some of the earlier cases of esopha­ treated previously with ranitidine ( 11 l ). duced sa livary lgA secretion ( 77) has geal Crohn's disease were treated surgi­ Impaired gastric emptying in Crohn'sdis­ been postulated to result in impa ired cally because of severe obstructive sy mp­ easc may result in the development of mucosa! defence against one o r more in­ toms or suspicion of neoplastic disease. nutritional deficits, growth failure in chil­ fectious agents. Recently, microbiologi­ Later, lower esophageal strictures ( 5), as d ren and impaired delivery of medica­ cal studies of the periodontal flora of well as cricopharyngeal Crohn's disease tions to the small and large intestine patients with inflammatory bowel dis­ (92), were reported to have been success­ ( 112). Gastric retention of cnteric coated ease have revealed unusual microorga­ fu lly managed with stricture dilatation. sulfasa lazine tablets has been noted ( 1l 3), nisms consistent with the genus Woline/la; Extension of Crohn 's disease into the and similar difficulties arc likely to re­ extracts and culture supernatancs of these respiratory tract has also been well docu­ sult from other such medications ad­ motile Gram-negative rods have revealed mented (93). This may not be too sur­ ministered in the treatment of Crohn's a serum mediated defect in neutrophil prising given the common developmental disease or its extraintcstinal manifesta­ chernotaxis having a possible role in the o rigins of the gastrointestinal and respi­ tions (eg. arthritis). This may be an im­ disease pathogenesis (82). ratory tracts and the recent evidence that portant consideration in clinical trials In the esophagus, isolated involve­ the immune system of the gastrointesti­ designed to assess the efficacy of a spe­ ment has been described but appears to nal tract is common to all mucosa! sur­ ci fi c treatment modality, including d is­ be rare. In this setting, the extension of faces (94 ). Upper airway obstruction and ease apparently loca lized to the more granu lomatous processes from the respi­ laryngeal involvement with granuloma­ distal small or large intestine. Recently, ratory tract and mcdiastinum must be tous inflammation have been described some consideration has been afforded excluded. Franklin and Taylor (83) first (95.96), as well as bronchial granulomas to the newer e t. :eric liquid formulations described isolated esophageal stricture (97). suppuration and bronch iectasis of 5-aminosalicylic acid ( 114). Parenteral and granulomatous esoph agi tis in three (98). noncaseating granulomatous pul­ nutrition may be used, but it is unlikely patients in 1950. Esophageal disease with monary infiltrates (99,100), and sul­ to resolve the disease process or a lter its Crohn's disease involving other sites in fasalazine associated pneumonitis ( JOl- natural history, particularly iffibrotic in­ the gastroin testinal tract was first re­ 105). Subclinical lung function abnor­ flammatory gastroduodcnal d isease is corded in 1954 (84 ). Another patient was malities have also been noted. includ­ already present. Since these patients may descr''..ied by Achenbach ct al (85), in ing abnormal pulmonary function tests be n utritionally depicted with significant 1956 as having stcnosis, multiple perfo­ ( 106- 108), impai red carbon monoxide weight loss, parenteral nutrition. espe­ rations and mediastinal abscesses. lnter­ diffusion ( [09), and a high incidence of cially prior to surgical intervention, may estingly, this patient also had perinea! latent lymphocytic alveoli tis defined by be essential for re:,uscitation. disease, e rythema nodosu m. pyoderma bronchoalveolar lavage ( 110). I( obstructive symptoms are due to gangrenosu m. arthritis and hepatic dys­ gastroduodenal stcnosis, a bypass gas­ function that resolved with csophagect­ TREATMENT trocnterostomy has generall y been rec­ omy. Later, additional patients were re­ The role of most treatment regimens in ommended (42, l 15, l 16). ln this setting, corded in 1968 and 1969 (86.87). while Crohn's disease of the esophagus, stomach the role of vagotomy has not been es­ the first documentation of noncaseating and proximal bowel is not known. Most tablished and may not offer any signifi­ esophageal gra nuloma was nored in [973 patients with oral lesions require no spe­ cant advantage over continuing pharma­ (5). A granulomarous histologic change cific oral treatment, although some find cologic treatment to suppress acid secre­ of the esophagus was also documented mild analgesics or Orabasc (Squibb; a mix­ tion. If a surgical approach is selected, using endoscopic biopsy in a patient with ture of gelatin. pectin, sodium carboxy­ however, worsening diarrhea may result. Crohn's colitis in 1977 (88). One year la­ methylcellulose in a mineral oil base) use­ especially if the in testine is already short­ ter, Crohn's disease of the esophagus was ful. Others find antacids helpful. Cheilitis ened from previous resections. More­ also associated with Barre tt's esophagus and other more significant lesions have over, the presence of a fistula, particularly ma patient with ilea! involvement (89). been treated with a combination of sys­ a duodenal fistula. is not a definitive in­ Although esophageal involvement was temic steroids. sulfasalazine, metronida­ dication for early surgical intervention previously tho ught to occur mainly in zole and azathioprine but their effective­ (49.54). Repair of fi stula, however, can older patients with Crohn's disease (90), ness is not obvious. Local inrralesional ster­ usually be accomplished in most patients a more recent retrospective survey of 500 oids have also been recommended (81). with excision and primary closure, al­ patients followed over a three year per­ For gastroduod enal involvement of though occasionally a two-stage repair iod in Belgium revealed nine patients Crohn 's with stcnosis, patients may re­ is necessary ( 49). with esophageal involvement having a spond to medical treatment with cortico­ mean age at diagnosis of 21 years (range steroids and parenteral nutrition ( 110). CONCLUSION 15 to 44) (91). ln most, extraintesrinal and possibly. measures (eg, ranitidine) Crohn's disease involving the upper manifestations, especially arthritis and directed toward the control of acid se­ gastrointestinal tract may be a significant genital ulceration. were common, and a cretion (4). In a recent pre liminary re- clinical problem in some patients with

CAN JGA SrnOENTEROL VOL 4 No I JANUARY/FEI\RUARY 1990 29 FRl:l::MAN

disease elsewhere in the small a nd large elsewhere in the intestine and to exclude creasingly recognized as a sig nificant mtesrine. ln occasional patients, disease in fectious causes. particularly if granu­ cause of morb1d1ty in some patients with may appear 'isolated' and initially involve lomas are observed. lf these studies arc C rohn 's d isease, the treatment options only the upper gastrointestinal tract. ln negative, prolonged follow-up may be re­ are limited and largely anecdotal More chis setring, a carcful assessment should quired to establish a diagnosis. Although focused studies of thts concern arc clearly be done to define if the disease is present uppe r gastrointestinal involvement is in- warra nted.

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Metronidazole-induced The spectrum of abnormal findings

30 CAN J GAsrnOENTL Rl)L Vo, 4 Nt) I JA!',UARY/FEBRt ARY 1990 Crohn's disease

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