Gut: first published as 10.1136/gut.16.4.249 on 1 April 1975. Downloaded from Gut, 1975, 16, 249-254

Oral manifestations of Crohn's disease

M. K. BASU, P. ASQUITH, R. A. THOMPSON, AND W. T. COOKE From the Departments of Oral Pathology and ofExperimental Pathology, Birmingham University, the Regional Immunology Laboratory, East Birmingham Hospital, and the Nutritional and Intestinal Unit, General Hospital, Birmingham

SUMMARY In a systematic study of 100 patients with Crohn's disease, 100 with ulcerative colitis, and of 100 normal subjects matched for age, sex, and denture status, nine patients with Crohn's disease, two with ulcerative colitis, and one normal control were found to have oral lesions. In Crohn's disease, the macroscopic and histological appearances resembled those encountered else- where in the gastrointestinal tract and their incidence was related to the activity of the disorder. The lesions in the other two groups were different macroscopically and histologically. Production of salivary IgA was found to be reduced in Crohn's patients with active bowel disease. It is suggested that the occurrence of oral lesions in patients with Crohn's disease might represent a local immunological reaction to oral antigens.

There have been a number of reports of 'apparently macroscopic and histological features; second!v, to specific' oral lesions in Crohn's disease (Dudeney study the interrelationship of mouth lesions with

and Todd, 1969; Issa, 1971; Schiller, Golding, other manifestations of Crohn's disease; and lastly http://gut.bmj.com/ Peebles, and Whitehead, 1971; Bishop, Brewster, to correlate them with haematological and bio- and Antonioli, 1972; Ellis and Truelove, 1972; chemical values and the results of salivary IgA Stankler, Ewen, and Kerr, 1972), which macro- estimations with a view to establishing their possible scopically and histologically resemble those found aetiology and pathogenesis. in the gastrointestinal tract. A retrospective analysis by Croft and Wilkinson (1972) of 332 Crohn's Materials and Methods also showed that 6% of such patients had

patients on September 25, 2021 by guest. Protected copyright. given a history of oropharyngeal ulceration. How- One hundred patients with Crohn's disease (38 men ever, patients without Crohn's disease commonly and 62 women) were examined for the presence of suffer from recurrent 'aphthous type' ulceration, oral lesions and their incidence was compared with which was found by Sircus, Church, and Kelleher that in two further groups, one consisting of 100 (1957) to have an incidence rate of 19-3% in a sample normal control subjects attending the Conservation of 1783 patients attending hospital outpatient and Department of the Dental Hospital, matched for general practitioner clinics. age, sex, and denture status, and the other consist- Oral lesions in general are often associated with ing of 100 patients with ulcerative colitis (42 men low serum iron and folate levels (Jacobs and Cavill, and 58 women). Based on the macroscopic appear- 1968; Dolby, 1972), findings which are common in ances corresponding with the previous descriptions patients with Crohn's disease (Swan, 1969; Dyer, of oral Crohn's lesions, four lesions were considered Child, Mollin, and Dawson, 1972). It has also been -cobblestone, ulcerative, tags, and erythema suggested that immunological mechanisms could be migrans. Recurrent aphthous type ulcers were not relevant to the aetiology of mouth ulcers (Lehner, included. 1972). Consequently, the finding of alterations in A of each oral lesion was carried out under humoral and cellular reactivity in many such patients local anaesthesia. Step serial 8 ,t-thick sections were (Kraft and Kirsner, 1971) may be relevant. prepared from paraffin-embedded specimens and The present study was carried out to compare the stained with haematoxylin and eosin for routine incidence of oral lesions in patients with Crohn's histological examination, with Gram's iodine with disease with that in controls and to study their fast green counterstain for microorganisms, with Received for publication 10 February 1975. PAS to disclose Candida albicans, with Weigert's 249 2 Gut: first published as 10.1136/gut.16.4.249 on 1 April 1975. Downloaded from 250) M. K. Basu, P. Asquith, R. A. Thompson, and W. T. Cooke stain for internal elastic lamina of the blood vessels, Finally, in 20 patients with Crohn's disease and 20 and with the silver cyanate reaction for peripheral age- and sex-matched volunteers (hospital staff and nerves (Rowles and Brain, 1960). laboratory personnel), a timed sample of saliva was In Crohn's patients the overall incidence of oral collected in an ice-cooled test tube from the right lesions was correlated with age, sex, primary site of parotid duct under acid drop stimulation and its the disease, and the presence of perianal and skin volume measured. The saliva was immediately lesions, and also with the serum levels of folate, B12, centrifuged at 8000 g for 10 minutes at 4°C and a iron, albumin, and seromucoids. drop of 1 in 100 merthiolate in distilled water added to the supernatant before being stored at -20°C. The level of total IgA was estimated within one month by a modified Mancini single radial diffusion technique (Fahey and McKelvey, 1965) using a monospecific IgA antiserum raised in rabbits and a normal control reference serum as standard. The parotid IgA secretion rate was then calculated.

Fig I http://gut.bmj.com/

Fig 3 on September 25, 2021 by guest. Protected copyright.

Fig 2 rig 4

Fig 1 Cobblestone lesion on the labial gingiva above Fig 3 Ulcerative lesion on of a patient with central and lateral incisor teeth of Crohn's patient. ulcerative colitis. Compare shape, size, and margin of the ulcer with figure 2. Fig 2 Ulcerative lesion on lateral margin of the tongue ofa Crohn's patient, showing linear shape, Fig 4 Tags on the inner side of the cheek of Crohn's hyperplastic margins, and depth. patient. Tongue at lower right corner. Gut: first published as 10.1136/gut.16.4.249 on 1 April 1975. Downloaded from

Oral manifestations of Crohn's disease 251 Results seen in two patients with ulcerative colitis were irregular in shape, with rolled margins, and were CLINICAL FINDINGS covered by a greyish-white slough (fig 3). The oral An increased incidence (p < 0-05) of mouth lesions tags seen in one patient with Crohn's disease were was found in Crohn's disease (9/100) compared with fleshy and inflamed (fig 4) and quite distinct to that that in patients with ulcerative colitis (2/100) and seen in the normal control, having the typical controls (1/100). The ages of the nine patients with appearance of leukoedema. The appearance of Crohn's disease ranged from 21 to 72 years and six erythema migrans in one Crohn's patient was were female. Involvement of both the small and large characteristic of that condition. intestine was present in eight patients, whilst one had Crohn's colitis only: perianal disease was found in HISTOLOGY six, and one had an eczematous skin lesion. Of the nine oral lesions in Crohn's disease only one showed epithelioid cell follicles in the lamina propria MACROSCOPIC APPEARANCES and submucosa (fig 5), some with giant cells. Al- Four patients with Crohn's disease had areas of though lymphoid follicles were found in one other overt hyperplasia of the oral with biopsy only (fig 6), the lamina propria and sub- an inflamed and deeply fissured surface, producing mucosa in all showed abnormal focal a cobblestone appearance (fig 1). The oral ulcers seen collections of lymphocytes and perivascular in- in three patients with Crohn's disease were deep, filtrates of mononuclear cells. Other non-specific linear in shape, and with a nodular hyperplastic signs of chronic inflammation, such as neuronal margin and clean base (fig 2). In contrast, the ulcers hyperplasia, lymphangiectasia, and oedema of the http://gut.bmj.com/ on September 25, 2021 by guest. Protected copyright.

Fig 5 Epithelioid cellfollicle in submucosa oforal Fig 6 Secondary lymphoidfollicle with germinal mucous membrane. Cobblestone lesion from Crohn's centre in submucosa ofanother cobblestone lesion from patient (x 200, H & E). Crohn's patient ( x 200 H & E). Gut: first published as 10.1136/gut.16.4.249 on 1 April 1975. Downloaded from 252 M. K. Basu, P. Asquith, R. A. Thompson, and W. T. Cooke

OralLesions Serum Folate Vitamin B12 Iron Seromucoid Albumin Mean Percentage Mean Percentage Mean Percentage > 150 mgll00 ml < 4 g/100 ml < 4 nglml < 160 pglml < 60 ug/ml With 12-68 ± 1-33 22 479 55 ± 3665 11 71-08 ± 3 58 44 75 78 Without 15-69 ± 5 78 16 413-34 ± 171-4 5 71-86 ± 13-85 37 26 34 Table Incidence ofabnormal serum levels in Crohn's disease with and without oral lesions

lamina propria and submucosa, were found regularly. large number of eosinophils with evidence of peri- In addition, of particular interest was the presence vascular deposition of fibrin. That from the control of focal collections of lymphocytes within the individual showed parakeratosis and acanthosis of stromal connective tissue (fig 7) and signs of acinar the surface with slight inflammation of atrophy and duct hyperplasia in the minor salivary the superficial layers of the lamina propria typical glands included in the biopsies. of leukoedema (Shafer, Hine, and Levy, 1974). In ulcerative colitis, the biopsies were quite Finally bacteria and Candida were not seen in the distinct with the lamina propria and submucosa histological specimens. containing a polymorphonuclear infiltrate and a HAEMATOLOGY AND BIOCHEMISTRY No significant differences were found in the mean values or in the incidence of low levels for serum folate, B12, or serum iron between Crohn's patients with and without oral lesions (see table). In contrast, an increased number of patients with oral lesions had raised serum seromucoid levels and low serum albumin levels compared with the incidence in patients without oral lesions (p < 0-05) (table I). http://gut.bmj.com/ SALIVARY IgA LEVEL The parotid secretion rates for healthy controls and for Crohn's patients showed no significant differ- ence. However, Crohn's patients with raised serum seromucoid and low serum albumin levels had significantly lower (p < 0 05) IgA secretion rates than patients with low serum seromucoid and high on September 25, 2021 by guest. Protected copyright.

Regression of Partid IgA secretion rate on

Serum Seromucoid in Crohns Patients

IgA Serum Albumin in Crohns Patients 01 . 2-50 3-00 3-50 4-00 4-50 5-.0 g 1100 ml Serum Albumin Fig 7 Minor salivary glandfrom Crohn's patient. Focal lymphocytic infiltration ofstromal connective Fig 8 Regression ofparotid IgA secretion rate on tissue with acinar atrophy and duct dilatation serum seromucoid and serum albumin in Crohn's (x 200, H & E). patients. Gut: first published as 10.1136/gut.16.4.249 on 1 April 1975. Downloaded from

Oral manifestations of Crohn's disease 253 serum albumin levels when compared with healthy disease, various mechanisms have been proposed. controls. The parotid IgA secretion rate of patients Crohn and Yarnis (1958) suggested that perianal with Crohn's disease also showed a significant lesions may be brought about by faecal contamina- regression (p < 0-05) when plotted against their tion and/or by the effects of gravitation. A retro- serum seromucoid and serum albumin levels (fig 8). grade flow in the lymphatic channels connecting the aggregations of lymphoid tissue of the ileum and the Discussion perianal region has also been suggested (Fielding, 1972). However, such mechanisms cannot be re- In this study, oral lesions occurred more commonly sponsible for the development of either the meta- in patients with Crohn's disease compared with the static lesions of the skin (McCallum and Kinmont, situation in normal controls and patients with ulcera- 1968; Mountain, 1970) or of the oral lesions. In tive colitis. The age range, sex distribution, and site Crohn's disease low serum albumin and high serum of disease in Crohn's patients with oral lesions were seromucoid levels are considered good indices of similar to those reported in the literature (Dudeney disease activity (Cooke, Fowler, Cox, Gaddie, and and Todd, 1969; Issa, 1971; Schiller et al, 1971; Meynell, 1958). Hence the present finding of a Bishop et al, 1972; Bottomley, Giorgini, and significant correlation between the presence of oral Julienne, 1972; Stankler et al, 1972; Varley, 1972; lesions in Crohn's patients and low serum albumin Eisenbud, Katzka, and Platt, 1972) and to those in and high serum seromucoid levels suggests that they the total sample of Crohn's patients examined, are related to active Crohn's disease. In contrast, suggesting that these factors were unimportant in the lesions were not related to a deficiency of folate, influencing the incidence of mouth lesions. B12, or iron, as reflected in serum levels of these In several respects the oral lesions macroscopic- substances. ally and histologically resembled those seen in the Finally, reduced secretion rates of parotid salivary gastrointestinal tract in Crohn's disease suggesting IgA have been found with increasing activity of the that they were due to the same disease process. bowel disease. This can be explained if it is postu- However, typical sarcoid-like granulomas were not lated that in active disease a transient transepithelial seen. Such granulomas are thought to be the most block to IgA develops in the parotid glands, similar useful histological sign of Crohn's disease, occurring to that which has recently been demonstrated in http://gut.bmj.com/ in 60% of resected bowel specimens (Williams, 1964; diseased epithelium of resected bowel specimens Morson, 1971; Cook, 1972). The failure to find them (Green and Fox, 1973). Alternatively in active in the biopsies of the mouth lesions may be related disease part of the parotid IgA could exist as to the small size of the biopsy. Also the incidence of polymers which would result in falsely low IgA granulomas varies from tissue to tissue with only estimates with the technique used. Finally, it could 19% occurring in rectal biopsies from patients with also be postulated that in patients with active

Crohn's disease (Dyer, Stansfeld, and Dawson, disease IgA plasma cells destined for the parotid on September 25, 2021 by guest. Protected copyright. 1970). gland are diverted to the site of maximum antigenic In the absence of sarcoid-like granuloma, an stimulation in the bowel. As IgA is thought to be aggregated pattern of lymphocytic infiltration of important in the defence of mucosal surfaces the lamina propria and the submucosa, some (Tomasi and Bienenstock, 1968), then the relative lymphocytes with germinal centres, perivascular lack of IgA in the mouth of patients with active infiltration of lymphohistocytic cells, and neuronal bowel disease may allow invasion of the oral mucous hyperplasia was found in the oral lesions; these membrane by the food or bacterial antigens in the features have been considered as good indicators of mouth (Ivanyi and Lehner, 1970), so producing an Crohn's disease (Morson and Dawson, 1972; Cook oral lesion. and Dixon, 1973). On this basis the histological features of the mouth lesions in our patients were References consistent with a Crohn's lesion. Of additional were the in Bishop, R. P., Brewster, A. C., and Antonioli, D. A. (1972). Crohn's interest findings minor salivary glands. disease of the mouth. Gastroenterology, 62, 302-306. These were similar to changes described in auto- Bottomley, W. K., Giorgini, G. L., and Julienne, C. H. (1972). Oral immunity such as Sjogren's disease, rheumatoid extension of regional enteritis (Crohn's disease). Oral Surg., 34, 417-420. arthritis, and (Whaley, Cook, M. G. (1972). The size and histological appearance of mesen- Williamson, Chisholm, Webb, Mason, and teric lymph nodes in Crohn's disease. Gut., 13, 970-972. Cook, M. G., and Dixon, M. F. (1973). An analysis of the reliability Buchanan, 1973), and, as far as we can ascertain, of detection and diagnostic value of various pathological they have not been reported previously in Crohn's features in Crohn's disease and ulcerative colitis. Gut, 14, disease. 255-262. Cooke, W. T., Fowler, D. I., Cox, E. V., Gaddie, R., and Meynell, To explain the extraintestinal lesions of Crohn's M. J. (1958). The clinical significance of seromucoids in Gut: first published as 10.1136/gut.16.4.249 on 1 April 1975. Downloaded from

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