Upper gastrointestinal tract Crohn's disease

: Crohn's disease may involve any site within the gastrointestinal tract. Usually pathology is present in the ileum and/or colon, but atypical presen tations may occur with apparently 'isolated' involvement of the oropharynx, esoph agus or gastroduodenum. lf changes typical of Crohn 's disease are detected in the upper gastrointestinal tract, then a careful assessment is required involving radiographic, endoscopic and histologic studies to determine if pathology is present in more distal intestine. In addition, microbiologic studies may be important to exclude infectious causes, especially of granulomas. If these studies are negative, prolonge; follow-up may be required to establish a diagnosis of Crohn's disease. Although upper gastrointestinal involvement is increasingly recognized as a sig nificant cause of morbidity in Crohn's disease, the treatment options arc limited, largely anecdotal and need to be the subject of detailed cpidemiologic investiga tion and clinical trials. Can J Gastroenterol 1990;4(1):26-32

A NY SITE WITHIN THI:: GASTROINTEST inal tract may be involved in Crohn's disease (I) lt is well recogni zed that U eal and/or colonic involvement arc most often present, but occasionally 'isolated' disease locali zed to o ne or more sites in the upper gastrointestin al tract occurs. Indeed , if involvement with Crohn'sd1sease is de fined by the presence of subtle endoscopic changes including aph thoid ulce ra tio ns o r histologic fe atures alone, rhe sto mach a nd duodenum appear to be relati vely common sites of Crohn's disease. C hanges in the esophagus have also been recorded but appear to be less frequen t. lf' isolated ' granulo matous disease is documented , however, carefu l ex· clusio n of o the r ca uses of granuloma is required. G enerally, this sho uld include an evaluation of the distal small and large bowel to determine if the mo re typical radiographic, endoscopic or hi stologic features of C ro hn 's di sease are present.

GASTRODUODENAL DISEASE
Frequency: So me of the ea rlies t re· po rts recognizing gastric involve ment in Croh n 's disease were recorded by Ross (2) in J949 andCo mfort etal(3)in 1950.
Since then , well over 100 pa tients have heen repo rted with granulomatous inammatory disease of the stom ach and duodenum attributed to C rohn's disease.
As th e majority of th ese reports have focused largely on clinically significant involve ment, estimated to be approx1· rnately 2 to 4% of all patients ( 4). the true frequency is likely to be much higher. Indeed. initial reports suggested that the prevalence of patients with documented Crohn's disease e lsew here in the gastrointestinal tract was no mo re than 7°{, (5)(6)(7). Subsequent studies. however, indicate that disease was r resen t in the upper gastroi n testi na l tract in over 20% (8.9). This reflects, in part, an in creased appreciation in recent years for the widespread, often segmental or focal nature of this inflammatory p rocess within the gastrointestinal tract. Moreover, the combined use of upper e nd osco p y and mucosa! biopsy has increased the incidence of recognition, even if the disease is clinically or radiograph ically 'silent' at this site. Clinical features: In m a ny patients, symptoms relating to the upper gastrointestinal tract m ay b e limited or frequently overshadowed hy diarrhea and other symp tom s associated with small or large intestinal disease. Even significant symptoms relating to resistant ulceration and progessive gastroduoden al stenosis may go unrecognized until later in the clinical course. ln this setting, marked nutritional disturbance and weight lo:,s are cor.,mon. in part reflecting the progressive im pairment of foo d intake and impaired gastric emptyi ng of nutrients into the small intestine. In some patients, the clinica l features of anorexia nervosa may be present ( 10.11 ). Symptoms related to gastric o utlet obstruction such as nausea and vo miting m ay result. Because of th e cicatrizing nature of this inflammatory process in the antral and pyloric region, the proximal stomach may appear di la ted with ret a ined food debris and sometimes bezoar for mation. Hemorrhage. especia ll y from deep ulceration. has been possibly incorrectly considered an uncom mon presentation for most granulomatous gastric disorders 112); in part, this idea may reflect a tendency to attribute the cause of ulceration to 'acid peptic' disease or commo nly prescribed ana lges ics used to m a n age abdominal pain or arthropathy. In addition, endoscopic biopsy. especially in this setting, is commonly not done since patients are usually young so that distinction from neoplastic disease is rarely difficult. If ulcers or erosions are present, however, endoscopic biopsy may reveal granulomas and o ther mo re typica l his-tolog1cal features of C ro hn's disease. In ad dition to blood loss, however. anemia may result from deficits o f iron o r folic acid due in part to reduced absorption from a diseased proximal small intestine. 'Isolated' gastric disease: In some patients, gastric involvement alone may occur ( 13.18). In these patients, pain may be a prominent sy mptom and although no obstructio n is evident, abnormal gastric emptying may still occu r. Diagnosis may be suggested by nuclear scans or by barium studies showing impaired e mptying of contrast; in the most extre me situations, a poorly distensible gastric antrum. som eti mes with aphthoid u lceration and 'cobblesto ning' o f antral folds with fissuring, ulceration and pyloric defo rmi ty may be present. In one report. the barium radiographic 'ram's horn' sign was described ( 19). In these pa tie nts, Croh n 's disease may later becom e evident in the more distal small and la rge intestin e. 'Isolated' duodenal disease: Isolated involvement of the proximal small intestine including th e duodenum may also occur (20)(21)(22)(23)(24). Most often evidence of such involvement is limited to focal inflammatory changes or isolated m ucosa! g ranulomas, with multinucleated giant cells o r loose aggregates and clusters of cpi the lioid ce lls. In o the rs. mo re severe changes may be present with multipl e and diffuse ste n otic sm all bowel segm ents. Such patients are prone to episodes of bowel obstruction, generalized malnutri tion and numerous specific nutrient deficiencies. The frequency of more clinically significant, extensive small bowel disease is not known. In o ne early study (25). based large ly on contrast radiographic exa minations. 18 of 330 patie nts with C ro hn 's disease seen from 1944 to 1970 were described as having m ore than diffuse jejuna I involvement. The early lite rature on Cro hn 's disease (26)(27)(28) also describes the laparotomy appearances of the small intesti ne in rare p atients characterized by diffuse and multiple miliary-like granulomatous serosal lesions; the proximal small bowel was also involved . In these patients, mic rob iologic studies, sp ecifi ca lly for Mycobacteriam tuberculosis were n egative. This e ntity was term ed 'miliary Crohn 's disease'; it was suggested that this Crohn's disease entity may represent an early stage of the di sease.
ln patients with duodenal disease, a concomitan t inflammatory change in the pa ncreas or biliary tract may be present. In thi s setting , bi liary tract sto nes o r sludge, as well as the reflu x of duodenal content into the pancreatic duct through an incompetent ampu lla. have been described (29)(30)(31). ln others, drug induced disease o f the p ancreas h as been reported, especially with su lfasa lazine (32). metronid azole ( 33) an d immunosuppressive agents. including azathioprine and 6-mercaptopurine (34-36). Alco ho l associa ted injury ca n also occu r in these patients. More recently. direct ampullary involvement with stenosis as well as common bile duct o bstruction have been recorded (37). ln addition, duodenal bezoar formation (38). and fistulous communica ti o n with the pa ncreatic duct h ave been described ( 39). Endoscopic features: Endoscopy may permit a better appreciation o f th e cha nges associated with Crohn's disease in the upper gastrointestinal tract, even ifir is apparently asympto matic (8,(40)(41)(42)(43)(44)(45). Gastric and duodenal u lcera tion, especia ll y linear or serpiginous, may be observed. The an trum may be poorly distensible with ai r insufflation, and rigid pyloric o r pylo roduodenal stenosis may prohibit passage of even 'ped iatr iccalibre' endoscopes. Macroscopic changes may also include a minimal colour alteration, either patchy o r diffuse. focal white nod ul es, a ph thoid u Ice ration o r erosio n with exudate and apparent mucosa] 'cobblestoning'. Strictures and fistulae from the stomach o r duode num into n earby intestin al loops o r the pancreatobiliary tract may be appreciated. More o ften, with the development of fi stulae, a coexistent inflam mato ry focus is present in an adjacent loop o f sm all or large bowel -in this setting, the fistu la is usually considered 'secondary' to the intestinal disease (46)(47)(48)(49)(50)(51)(52)(53)(54). Often, upper endoscopy is limited in its ability to determine th e fistula opening which usually appea rs o nly as a small , some times erythematous, raised dimple with ex udate on a raised cluster o f gastric folds (55). The most common site for a fistula recognized at endoscopy is the greater curvature of the stomach . usu ally from the FREEMAN splenic flexure of the colon. ln patients with a prior ileocolonic resection. however. fistulous commu nication berween the anastomosis and the descending duodenum may be seen . Routine bari um or gascrograffin contrast studies remain the most useful for diagnosis. although contrast introd uced d irectly through an endoscopic catheter m ay also be used. Altho ugh a gastrocolic fistu la is most common (49)(50)(51)(52)(53), other causes of fistula should also be considered by the endoscopist in patients with Crohn 's disease, including carcinoma of the colon and stomach as well as lymphoma (56).
Histologic features: Biopsies from normal appearing or grossly abno rm al gastric mucosa often reveal no nspecific inflammatory changes; foca l neucrophilic infiltrates and mulcinucleated giant cells or cpithclioid cell clusters may a lso be seen, and may be more suggestive of possible Croh n's di sease. The detection of granulomas is not specific for Crohn's disease, especially if disease is not apparent elsewhere in the intestinal tract. However, their initial detection in a patient not known co have Croh n 's disease should lea I to endoscopic and radiogra phic assessments of th e small an d large bowel. H istological distinction of the granulomara from o ther en ti ties, including sa rco idosis, is often not possible wi th 'isolated ' gastric involvemen t, and diagnosis may be established o nl y after fu rther investigations including pulmonary assessment, liver and possibly lymph node biopsy (57)(58)(59)(60). In addition , ocher en tities should be excluded in the presence of isolated' gastric disease. such as foreign bodies (eg, suture-associa ted), tuberculosis, hiscoplasmosis and syphili tic gastric involvement as well as ocher infectious causes (59-6 1 ). Distinction from gastric neoplastic disease, although it is not apparently increased in Crohn's disease, is im portant. ln the pediatric patient, chro nic gra nulo m aro us disease may be a special consideration, especially if gastric o utlet o bstructio n is present ( 62 ). The sy nd rome o f necrotizing granulomatous gastritis seems sufficiently distinct from the pathological changes in Croh n 's disease such that differentiation is not usually difficu lt (63). If endoscopic or suction biopsies o f the d uoden um o r proximal jejun um reveal 'isola ted' gran-ulomas, exclusion of other causes is warran ted, particu la rly for infectious d iso rders, as their detection may alter therapy (6l). In the absence o f granulomas. Crohn 's disease may still be present, especially if a constellation of acute, particularly focal , neutrophuic inflammatory changes o r crypt abscesses are present ( 45). In occasional patients, small bowel biopsies m ay reveal changes more typical of celiac sprue with mucosa! vi llus atrophy and crypt hyperplasia (45). These mucosa! biopsy changes may be patchy o r d iffuse and va riable in the degree of severity ranging from mild to severe (64). Variable changes m ay be appreciated only if multiple small bowel si tes are b iopsied . A number of reports have recorded the coexistence of celiac sprue and inflammatory bowel disease in the same patients (65); some likely represent Crohn's disease alone. Differentiation of Crohn 's from celiac sprue may be especially difficult in some patients, particularly if C rohn's disease is not read ily evident in the mo re distal small or large bowel; moreover, disorders characterized by spontaneous remissio ns may be difficult to distinguish even with clinical improvement on a gluten-free diet. While there arc o ther causes of a 'fl at' small intestinal biopsy (64), the acute nature of the inflammatory process with polymorphonuclear leukocytes and crypt abscesses may favour a diagnosis of C rohn 's disease (4 5). In add ition, other entiti es should be considered if an acute inflammato ry process is present without granulomas, including Zollinger-Ellison syndrome (66) and so-called 'benign nongranulomatous jej unitis', an entity also associated with celiac sprue (67). Infectiou s agen ts, especia lly if they are common in a specific geographic area, deserve careful exclusion. ln the au thors' institutio n , for example, a commonly recognized agent in patients with gastroin testinal disease is Yersinia enterocolitica; in the authors' studies, endoscopic and histologic changes in the upper gastrointestinal tract have been frequent (68). Finally, the possibility of lymphoma in the proximal small intestine must be considered ; this distinction may be especially d ifficult because of the frequent presence of ulcerated and inflamed small intestine in lymphoma and the focal nature o f the lymphomatous infiltrates in some patients (69-72).

OROPHARYNGEAL AND ESOPHAGEAL DISEASE
Crohn 's disease occasionally involves th e mu co us membranes of the oropharynx and esophagus. Rarely, the re· spiratory tract may be involved, distinct fro m sa rcoidosis o r infectious disorders such as tuberculosis (58)(59)(60). Granulomatous inflammation of the mino r salivary gland ducts may also occur, causing sublingual cystic lesions due to d uct rupture and mucocele formation (73). Usually, involvement of the oropharyn x or esoph agus occurs in conjunction with evidence of disease elsewhere, particularly ilcoco· Ionic or perianal disease. Often the symp· toms are minim al but some patients may complain of painful oral ulce rs, or frequently dysphagia or odynophagia. Sometimes these sy mpto ms predominate over bowel symptoms and result in reduced food in take. malnutrition and weight loss.
O ral lesions in C ro hn 's disease were first reported in 1969 (74). with isolated disease o f the mou th in 1972 (75). ln the oro pharynx , superficia l o r epi the lial ulceration is re latively frequent (at least 10%) compared to th e less common changes of pai nfu l swelling and ulceration of the buccal mucosa, as well as the e rythematous gingival hyperplasia associated wit h his tol ogica lly documented gran ulo m atous infl ammatory disease (less than l %). Other described changes include angular chei li ci s, mucosa! tags or cobblesto ning of the oral mu· cosa and h ype rplastic gingival lesions (76)(77)(78)(79). Finally, the changes associated with nu trie nt deficiency and the effects of medications, including the Stevens· Jo hnson sy ndro me . may occur.
ln some patients, the pathology may be limi ted to th is si te or be the initial clinical manifestatio n years before the disease is detected elsewhere in the gas· troi n testin al tract (80,8 1). In such patients, conside ration sho uld be given to such entities as Behcet's sy nd rome if other clinical featu res of th is d isorder are present, such as genital ulceration. In addition , microbiologica l ca uses oforal ulcer· ation require exclusio n. notably Y encerocolitica, an infectious agen t that has been associated with a clinical sy ndro me of ilcocolitis similar to Crohn 's disease (68). The pathogenesis of the oral lesions in Crohn's disease remains unknown. Reduced sa livary lgA secretion ( 77) has been postulated to result in impa ired mucosa! defence against o ne o r more infectious agents. Recently, microbiological studies of the periodontal flora of patients with inflammatory bowel disease have revealed unusual microorganisms consistent with the genus Woline/la; extracts and culture supernatancs of these motile G ram-negative rod s have revealed a serum mediated defect in neutrophil chernotaxis having a possible role in the disease pathogenesis (82).
In the esophagus, isolated involvement has been described but appears to be rare. In this setting, the extension of granu lomatous processes from the respiratory tract and mcdiastinum must be excluded. Franklin and Taylor (83) first described isolated esophageal stricture and granulomatous esoph agi tis in three patients in 1950. Esophageal disease with Crohn's disease involving other sites in the gastroi n testinal tract was first recorded in 1954 (84 ). Another patient was descr''..ied by Achenbach ct al (85), in 1956 as h aving stcnosis, multiple perforations and mediastinal abscesses. ln terestingly, this patien t also had perinea! disease, e rythema nodosu m. pyoderma gangrenosu m. arthritis and hepa tic dysfunction th at resolved with csophagectomy. Later, additional patien ts were recorded in 1968 an d 1969 (86.87). whi le the first documentation of noncaseating esophageal gra nuloma was nored in [973 (5). A granu lomarous histologic ch ange of the esophagus was also documented using endoscopic biopsy in a patient with Crohn's colitis in 1977 (88). One year later, Crohn's disease of the esophagus was also associated with Barre tt's esophagus ma patient with ilea! invo lvement (89).
Although esophageal involvement was previously tho ugh t to occur mainly in older patients with Crohn 's disease (90), a more recent retrospective survey of 500 patients followed over a three yea r period in Belgium revealed nine patients with esoph agea l involvement having a mean age at diagnosis of 2 1 years (range 15 to 44) (91). ln most, ex traintesrinal manifestations, especiall y arthri tis and genital ulceration. were common, and a history of tuberculostatic or anti herpetic therapy was frequent.
Some of the earlier cases of esophagea l Crohn's disease were treated surgically because of seve re obstructive sy mptom s or suspicion of n eoplastic disease. Later, lower esop hageal strictures ( 5), as we ll as cricopharyngeal Crohn's disease (92), were reported to have been successfu lly managed with stricture dilatation.
Extension of Crohn 's disease into the respiratory tract has also been well documented (93). This may not be too surprising given the common developmental o rigins of the gast rointestinal and respiratory tracts and the recent ev idence that the immune system of the gastro intestinal tract is common to all mucosa! su rfaces (94 ). Upper airway obstruction and laryngeal involvement with granulomatous inflammation have been described (95.96), as well as bronchial granu lomas (97). suppuration and bronch iectasis (98). noncaseati ng granu lomatous pulmonary infiltrates (99,100), and su lfasalazine associated pneumonitis ( JO l- 105). Subclini cal lung function abnormali ties have also been noted. including abnormal pulmonary function tests ( 106-108), impai red carbon monoxide diffusion ( [09), and a h igh incidence of latent lymphocytic alveoli tis defined by bronchoalveolar lavage ( 110).

TREATMENT
The role of most treatment regimens in Crohn's disease of the esophagus, stomach and proximal bowel is not known. Most patients with o ral lesions require no specific o ral treatment, although some find mild analgesics or Orabasc (Squibb; a mixtu re of gelatin. pectin, sodiu m carboxymethylcellulose in a mineral oil base) useful. Others find antacid s helpful. C heilitis and other more sig nificant lesions have been treated with a combination of systemic steroids. sulfasalazine, metronidazole and azathioprine bu t their effectiveness is not obvious. Local inrralesional steroids have also been recommended (8 1).
For gastroduod enal involvement of Crohn 's with stcnosis, patients may respond to medical treatment with corticosteroids and parenteral nutrition ( 110). and possibly. measures (eg, ranitidine) directed toward the con trol of acid secretion (4). In a recent p re liminary re-CAN J GASrnOENTEROL VOL 4 No I JANUARY/FEI\RUARY 1990 Crohn's disease port, omeprazolc appeared to provide symptomatic benefit in certain patients treated previously with ran itidine ( 11 l ). Impaired gastric emptying in Crohn'sdiseasc may result in the development of nutritional deficits, growth failure in child ren and impaired delivery of medications to the small and large intestine ( 112). Gastric retention of cnteric coated sulfasa lazine tablets has been noted ( 1 l3), and similar difficulties arc likely to result from other such medications administered in the treatment of Crohn's disease or its extraintcsti nal manifestations (eg. arthritis). This may be an important consideration in clinical trials designed to assess the efficacy of a speci fi c treatment modality, including d isease apparently loca lized to the more distal small or la rge intestine. Recently, some consideration has been afforded to the newer e t. :eric liquid formulations of 5-aminosalicylic acid ( 114). Parenteral nutrition may be used, but it is unlikely to resolve the disease process or a lter its natu ral history, particularly iffibrotic inflammatory gastroduodcnal d isease is already present. Since these patients may be n utritionally depicted with significant weight loss, parenteral nutrition. especially prior to surgical intervention, may be essential for re:,uscitation.
I( obstructive symptoms are due to gastrod uodenal stcnosis, a bypass gastrocnterostomy has genera ll y been recommended (42, l 15, l 16). ln this setting, the role of vagotomy has not been established and may not offer any significant advantage over continuing p harmacologic treatment to suppress acid secretion. If a surgical approach is selected, however, worsening diarrhea may result. especially if the in testine is already shortened from p revious resections. Moreover, the p resence of a fistula, particularly a duodenal fist ula. is not a definitive indication for early surgical intervention (49.54). Repair of fistula, however, can usually be accomplished in most patients with excision and p rimary closu re, although occasionally a two-stage repair is necessary ( 49