The Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai 980

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1 Tohoku J. exp. Med., 1977, 123, Clinical Observations on Ulcerative Colitis HIKARU WATANABE, NOBUO HIWATASHI and SHOICHI YAMAGATA The Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai 980 WATANABE, H., HIWATASHI, N. and YAMAGATA, S. Clinical Observations on Ulcerative Colitis. Tohoku J. exp. Med., 1977, 123 (3), Based on the clinical results in 159 cases of ulcerative colitis experienced in our Department during the years , various clinical aspects such as incidence, symptoms, clinical findings, complications, treatment and prognosis were in vestigated. From- these observations, the following results were obtained: 1) Ulcerative colitis is not as rare as previously considered. It is slightly female predominant and seen most often in adolescents and adults. However, one of the most interesting findings is the secondary increase in incidence in older people, producing a bimodal curve. 2) One third of the total cases of ulcerative colitis belongs to the category of proctitis at the time of diagnosis. 3) Classical ulcerative colitis such as total colitis and left-sided colitis is characterized by mucous bloody stools as its chief symptom and often accompanied by fever, loss of weight, a rise in blood sedimentation rate, anemia, leucocytosis, hypoproteinemia, lowering of A/G ratio and hypopotassemia. These fingings, except for bloody stool, were not commonly found in proctitis. However, findings of procto sigmoidoscopy, cytologic examination, biopsy and radiological examination between classical ulcerative colitis and proctitis were similar. On the other hand, the lesion progressed to a part or all of the colon in 7 of 38 cases (18%) of proctitis during the observation period. Proctitis is, therefore, thought to be a part of ulcerative colitis. 4) The evaluation of medical treatment discloses that remission was obtained in 21 of 46 cases (46%) of total colitis, in 24 of 35 cases (69%) of left-sided colitis and in 31 of 38 cases (82%) of proctitis. Surgical intervention became necessary in 24 of 46 cases (52%) of total colitis, in 5 of 29 cases (17%) of left-sided colitis and in only one of 31 cases (3%) of proctitis. 5) Follow up studies revealed the recurrence of symptoms in many cases, although most patients were capable of maintaining normal lives. ulcerative colitis; proctitis Recently, the gradual increase in the frequency of ulcerative colitis cases as well as a greater concern for intestinal diseases has initiated a wide recognition of ulcerative colitis in Japan from both the clinical and epidemiological points of view. We have experienced 159 cases of ulcerative colitis at the Third Department of Internal Medicine, Tohoku University Hospital, during the last 22 years. We have, therefore, undertaken an investigation of ulcerative colitis in Japan on the basis of clinical results in these cases in order to clarify the various clinical aspects, Received for publication, December 13, This paper was presented at the 62nd Annual Meeting of the Japanese Society of Gastroenterology, held in Tokyo on March 29-31, This investigation was supported in part by grant from the Ministry of Public Welfare. 197

2 198 H. Watanabe et al. such as frequency, symptoms, clinical findings, complications, treatment prognosis. The present paper describes our results and conclusions from these observations. SUBJECTS AND METHODS The 159 cases of ulcerative colitis detected at our department during a 22-year period, , were included in our study. The diagnostic criteria provided by the Investigation and Research Committee for Ulcerative Colitis (Organized by the Japanese Ministry of Public Welfare in 1973) were used to classify the 159 cases into four anatomic types according to the extent of the lesions. Subsequently, comparative studies between total and left-sided colitis and proctitis were carried out with special attention to proctitiṣ Frequency RESULTS AND COMMENTS Ulcerative colitis was detected in 159 cases (0.15%) among 102, 519 outpatients (Table 1). This frequency is higher than formerly considered for Japan. When the patients were classified according to the extent of the lesion, 57 patients had total colitis, 57 left-sided colitis, 44 proctitis and one segmental colitis. However, during the observation of 38 cases, proctitis progressed into left-sided and total colitis in 4 and 3 patients, respectively, accounting for 18% of the 38 patients TABLE 1. Incidence of ulcerative colitis, Crohn's disease and tuberculosis of the colon in Tohoku University Hospital ( ) and

3 Clinical Observations on Ulcerative Colitis 199 initially diagnosed as proctitis. Thus, one third of the total patients belonged to the category of proctitis at the time of the initial examination. Sex of the patients There were 79 male and 80 female patients. The frequency of the 146 patients since 1962, calculated with reference to the total number of outpatients during the same period, showed a ratio of 0.20% for males and 0.29% for females. Age of the patients The age distribution at the initial examination displayed a bimodal curve with the primary and secondary peaks in the 2nd and 6th decades in male patients; a unimodal curve with the peak in the 4th decade in females; and a unimodal curve with the peak in the 3rd decade for the combined (Fig. 1). The age-specific frequency of the 146 patients since 1962, calculated from the total outpatients, revealed a bimodal curve in males with peaks in the 2nd and 6th decades, a bimodal curve in females with the peaks in the 4th and 8th decades, and a bimodal curve in all patients with peaks in the 2nd and 8th decades (Fig. 2). These results are in accord with those of Evans and Acheson (1965) and Burch et al. (1969). Retrospective classification of the age at which bloody stools were first noticed (the age of onset) also demonstrated a bimodal curve. Comparison of Fig. 1. Age distribution of ulcerative colitis ( ). œ--- œ, male 79 cases; ü- ü, female 80 cases; œ-- œ, total 159 cases. Fig. 2. Frequency of ulcerative colitia, as calculated on the basis of number of outpatients in separate age groups ( ). œ--- œ, male 71 cases; ü- ü female 75 cases; œ - œtotal 146 cases. Number of outpatients is 59,599.

4 200 H. Watanabe et al. Fig. 3. Comparison of frequency of total and left-sided colitis with that of proctitis, as calculated on the basis of number of outpatients in separate age groups ( ). œ- œ total and left-sided colitis 105 cases; œ-- œ., proctitis 40 cases. Number of outpatients is 59,599. patients with total and left-sided colitis with those with proctitis revealed that the former presented a curve with the primary peak in the 2nd decade and a low peak in the 8th decade, while the patients with proctitis showed a bimodal curve with two similar low peaks in the 2nd and 6th decades (Fig. 3). It must be noted that children under the age of ten years were omitted from this portion of this report, since the number of patients and outpatients were too limited to be significant. Occupation of the patients The 65 male patients consisted of 25 (38%) students; 21 (32%) physical laborers; 11 (17%) office workers e.g., teachers, doctors, etc.; and 6 (9%) those engaged in commerce. The 69 females included 33 (48%) unemployed women including housewives; 18 (26%) physical laborers, e.g., women working on farms, factories, fisheries, etc.; 11 (16%) office workers and teachers; 4 (6%) those engaged in commerce; and 3 (4%) students. Blood type groups of the patients Of the 94 patients investigated for their blood types, 40 patients were of group A (42%), 16 of group B (17%), 29 of group 0 (31%) and 9 of group AB (10%)

5 Clinical Observations on Ulcerative Colitis 201 Symptoms Precursory symptoms of 109 patients with total and left-sided colitis were mucous bloody stools in 88 patients (81%) and abdominal pain in 12 (11%). In 42 patients with proctitis, 35 (83%) had mucous bloody stools, 7 (17%) had diarrhea, and 6 (14%) had abdominal pain. At the initial examination of 94 patients with total and left-sided colitis in the active stage, mucous bloody stools were observed at 100%, diarrhea at 54%, abdominal pain at 44%, tenesmus at 20%, and emaciation at 14% (Table 2). In 42 patients with proctitis, mucous bloody stools were observed at 98%, diarrhea at 24%, and abdominal pain at 21% (Table 2). Namely, mucous bloody stools followed by diarrhea and abdominal pain are thought to be the most common symptoms in the active stage of ulcerative colitis, regardless of the extent of the lesion. TABLE 2. Symptoms of ulcerative colitis ( ) Clinical findings Laboratory findings. The number of patients showing fever above 37.5 Ž, weight loss by 15% or more, five or more diarrheal stools a day, leucocytosis, hypoproteinemia with the serum total protein of less than 6.4 g/100 ml, decreased

6 202 H. Watanabe et al. TABLE 3. Laboratory findings of ulcerative colitis ( ) A/G ratio, and hypopotassemia with the serum potassium of less than 3.5 meq/liter were frequent in patients with total and left-sided colitis than in patients with proctitis. The group of total and left-sided colitis also included many patients with increased erythrocyte sedimentation rates and anemia, irrespective of sex (Table 3). Endoscopic findings. Proctosigmoidoscopy in many patients with total and leftsided colitis in the active stage disclosed rough or granular mucosa and numerous erosions often coated with pus (Table 4). Proctosigmoidoscopy in patients with proctitis gave similar findings, which were indistinguishable from those seen in total and left-sided colitis (Table 4). The recently introduced procedure of fiberoptic colonoscopy now facilitates the visualization of longer segments of the colon (Watanabe 1972, Watanabe et al and 1975). The fiberoptic colonoscopy findings in the groups with total and left-sided colitis did not differ greatly from the proctosigmoidoscopic findings, except that pseudopolyposis was increased and TABLE 4. Proctosigmoidoscopic findings of ulcerative colitis ( )

7 Clinical Observations on Ulcerative Colitis 203 TABLE 5. Colonoscopic findings of ulcerative colitis ( ) replaced by rough or granular mucosa and erosions (Table 5). Cytologic findings of the mucosal secretion. Cytologic examination of the mucosal secretion were performed using rectal swabbing method or modified colon brush method. Cytologic examination of patients with total and left-sided colitis in the active stage disclosed a tremendous number of neutrophils often associated with the appearance of plasma cells, multinucleated giant cells and occasionally reticulum cells (Table 6). Similar findings were found in patients with proctitis (Table 6). These abnormalities were rarely observed in the stage of remission (Table 6). Thus, these cytologic findings are thought to be characteristic of the active stage of ulcerative colitis (Watanabe 1969). TABLE 6. Cytologic findings of ulcerative colitis ( ) In contrast, in 50 patients with irritable colon in which biopsy showed normal colonic mucosa, no plasma cells were seen, although multinucleated giant cells were seen in only one patients (2%) and a tremendous number of neutrophils was noted in 6 patients (12%). However in 2 patients with intestinal tuberculosis, a great number of neutrophils was seen in both patients, and plasma cells and multinucleat ed giant cells in one patient. In 9 patients with amebic colitis, a tremendous number of neutrophils was observed in 2 patients (22%), plasma cells and multinucleated giant cells in one (11%). Entamoebae histolyticae were noticed in all patients with amebic colitis by cytologic examination. In 82 patients with cancer of the colon and rectum, numerous neutrophils were also seen in 20 patients

8 204 H. Watanabe et al. Fig. 4 (upper). A tremendous number of neutrophils. May-Giemsa stain. Fig. 5 (lower). A multinucleated giant cell. May-Giemsa stain. (24%), plasma cells in 5 patients (6%) and cancer cells in 77 patients (94%). Therefore, the above cytologic findings are thought to be not pathognomonic to ulcerative colitis, but represent inflammation of the large intestine (Watanabe 1969). Figs. 4 and 5 show a tremendous number of neutrophils and a multinucleated giant cell, respectively. Fig. 6 shows a plasma cell and a reticulum cell. Histologic findings of the biopsy specimens. Histologic examination of biopsy specimens from patients with total and left-sided colitis in the active stage revealed that goblet cells disappeared (goblet cell depletion) but crypt abscess and erosions developed in association with inflammatory changes in the mucosa, and the regeneration of the intestinal glands and the resultant disarrangement of the glands were often observed at the same time (Table 7). These findings were also found in the

9 Clinical Observations on Ulcerative Colitis 205 Fig. 6. A plasma cell (left) and a reticulum cell (right). May-Giemsa stain, TABLE 7. Histologic findings of the biopsy specimen of ulcerative colitis ( Th) group of patients with proctitis (Table 7). In the stage of remission, however, these abnormalities were rarely found except in the regenerated and disarranged glands (Table 7). In a few specimens, however, the above-mentioned abnormalities in the active stage remained in some limited areas even in the remission stage (Table 7). Figs. 7 and 8 show histologic findings of biopsy specimens in the active stage and Fig. 9 shows those in the stage of remission. Radiologic findings. Recently the one-stage double contrast method in the colon and rectum has been introduced. The radiologic findings by the one-stage double contrast method in the colon of patients with total and left-sided colitis in the active stage during the past 6 years showed that fine granular patterns and small visible niches often appeared (Table 8). However, similar findings were seen

10 206 H. Watanabe et al. Fig. 7. Histology of the biopsy specimen in the active stage of ulcerative colitis, showing inflammatory changes in the mucosa. Hematoxylin and eosin stain. in the rectum of these patients (Table 8). These findings, however, were also very frequently found in the patients with total and left-sided colitis in the stage of remission (Table 8). Therefore, it appeared to require discretion to determine the stage of disease, based on the radiologic findings by the one-stage double contrast method. On the other hand, fine granular patterns and small niches are often present in the rectum of patients with proctitis when examined in detail (Table 8). Therefore, when examined carefully, these findings can be detected even in proctitis. Figs. 10 and 11 show fine granular patterns and small visible niches in the colon of patients with total colitis and those in the rectum of patient with proctitis, respectively. Complications Of 114 patients with total and left-sided colitis, 39 were complicated pseudopolyposis, 3 by toxic megacolon, 8 by arthritis (arthralgia), 3 by stomatitis, one by erythema nodosum, and one by erythema exudativum multiforme, while of 44 patients with proctitis, only 6 were complicated by pseudopolyposis, and 2 by arthritis (arthralgia) (Table 9). Hence, the frequency of complications, except for pseudopolyposis, seems lower in Japan than in the European countries and in the U.S.A. In three patients complicated by arthritis (arthralgia), RA tests were examined and were negative in all three. Of 43 patients undergoing RA tests, 2 gave positive results, but had no arthralgia (Table 3). No malignant degeneration occurred in our patients. by

11 Clinical Observations on Ulcerative Colitis 207 Fig. 8. (upper). Histology of the biopsy specimen in the active stage of ulcerative colitis, showing crypt abscesses. Hematoxylin and eosin stain. Fig. 9 (lower). Histology of the biopsy specimen in the stage of remission of ulcerative colitis, showing regeneration of the glands. The epithelium was occupied by hypertrophic goblet cells and cell infiltration much decreased. Hematoxylin and eosin stain. TABLE 8. Radioloyic findings (the one-stage double contrast method) of ulcerative colitis ( )

12 208 H. Watanabe et al. Fig. 10 (left) Radiologic findings by the one-stage double contrast method in the colon of a patient with total colitis, showing fine granular patterns and small visible niches. Fig. 11 (right). Radiologic findings by the one-stage double contrast method in the rectum of a patients with proctitis, demonstrating fine granular patterns. TABLE 9. Complications of ulcerative colitis ( )

13 Clinical Observations on Ulcerative Colitis 209 TABLE 10. Results of the medical treatment ( ) * Including 4 cases of proctitis developed into left-sided colitis, 3 cases of proctitis developed into toal colitis, and 3 cases of left-sided colitis developed into the total colitis during the observation period. TABLE 11. Frequency of surgical treatment ( ) Results of the medical treatment and the frequency of surgical treatment Follow up investigations of 110 patients treated conservatively were carried out to evaluate the treatments. Remission was achieved in 66% of them, no change or aggravation was seen in 32%, and 3% died (Table 10). When these patients were classed by the extent of lesion, remission was achieved in 82% of 38 patients with proctitis, while it was achieved in 69% of 35 patients with left-sided colitis, and in 46% of 46 patients with total colitis (Table 10). In follow up studies of 110 patients, the frequency of surgical treatment were checked. Surgical resections were performed in 27% immediately after termina tion of the observation (Table 11). When these patients were classed by the extent of lesion, one of 31 patients (3%) with proctitis, 5 of 32 patients (16%) with left-sided colitis, and 24 of 46 (52%) patients with total colitis received the surgical resection (Table 11). Of 29 patients who received surgical resection, 4 with total colitis died shortly after the surgery. When the frequency of surgical resections was examined employing diagnostic criteria, i.e. extent of lesion, severity, clinical courses and macroscopic findings, provided by the Investigation and Research Committee for Ulcerative Colitis (1975) and by the combinations of the criteria, the frequency was high not only in patients of the total colitis type, but also in patients of the severe type, i.e. the acute fulminating or chronic continuous type, those with pseudopolyposis and those of combined types (Table 12). Alterations in the serum protein fractions of 12 patients with severe and

14 Fig 210 H. Watanabe et al. TABLE 12. Number of cases and number of colectomy cases in each type classed according Investigation and Research Committee for Ulcerative Colitis ( ) ( ): Number in brackets represent numbers of. 12. Alterations in serum protein fractions. œ--- œ, cases of severe and/or moderate total and/or left-sided colitis which received surgical resection (12 cases); ü --- ü, cases which had similar lesions but achieved remission (12 cases). moderate total and left-sided colitis who eventually received surgical resections were compared with those of 12 patients who had similar lesions but achi eved remissions by medical treatment. In the patients of the latter group, increased ƒ 1 - and ƒ 2- globulin on admission tended to be within the normal range at discharge, while in the former group, increased globulins tended to decrease but did not return to normal, and no tendency was found in the behavior of ƒá -globulin either in terms of percentage or in terms of g/100 ml (Fig. 12).

15 Clinical Observations on Ulcerative Colitis 211 to the types of diseases, included in the diagnostic criteria which had been provided by the coleetomized cases in each group. Fig. 13. Prognosis of ulcerative colitis: Relationship between bloody stools and the year-period after the initial examination ( ). œ, cases of continued bloody stools;?, cases of occasional bloody stools; ü, cases in which bloody stools disappeared. Fig. 14. Prognosis of ulcerative colitis: Relationship between states of rehabilitation and the year-period after the initial examination ( ). o, patients who had hardly worked; o, patients who had returned to their occupation or to their housekeeping work. Prognosis The patients who received no surgical resections were investigated for their prognosis. The majority of patients were followed in the outpatients' department

16 212 H. Watanabe et al. and some others were investigated by the questionaires. There were no any patients who had bloody stools that could be considered as an index of recurrence, irrespective of the extent of lesion or the period of years after the initial examination (Fig. 13). The investigation of their states of rehabilitation disclosed that all of them had returned to their occupation or to their house-keeping works, except for some patients with total colitis, one patients with left-sided colitis complicated by SMON (subacute inyelo-optico-neuropathy) and one with proctitis complicated by SMON (Fig. 14). Thus, it appeared that rehabilitation would be possible for those patients who had achieved remissions by medical therapy, except for some patients with total colitis. DISCUSSION An analysis of 159 patients of ulcerative colitis detected during 22 years was carried out with special reference to proctitis. As a result, some interesting conclusions stated above were obtained. Since these conclusions are drawn on the basis of the results in all patients experienced at single department during an extended period, they are certain to represent exactly the ulcerative colitis in Japan in a different sense from the results compiled by nationwide collective studies by using questionaires. Recently, the importance of ulcerative colitis has been recognized in Japan and the Investigation and Research Committee for Ulcerative Colitis has been organized and started its action on a nationwide scale. Accordingly, it is believed that epidemiology of ulcerative colitis in Japan will be studied in more detail. It might be expected that differences or similarities between Japanese and those in other countries would be elucidated clearly. References 1) Bur-h, P.R.J., de Dombal, F.T. & Watkinson, G. (1969) Aetiology of ulcerative colitis. U. A new hypothesis. Gut, 10, ) Evans, J.G. & Acheson, E.D. (1965) An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut, 6, ) Farmer, R.G. & Brown, C.H. (1966) Ulcerative proctitis: course and prognosis. Gastroenterology, 51, ) Folley, J.H. (1970) Ulcerative proctitis. New Engl. J. Med., 282, ) Investigation and Research Committee for Ulcerative Colitis (1975) The diagnostic criteria of ulcerative colitis. Jap. med. J., No. 2673, pp (Japanese) 6) Lennard-Jones, J.E., Copper, G.W., Newell, A.C., Wilson, C.W. & Jones, F.A. (1962) Observations on idiopathic proctitis. Gut, 3, ) Sparberg, M. (1968) Ulcerative proctitis. Texas J. Med., 64, No. 6: ) W atanabe, H. (1969) Ulcerative disease of the large bowel: from th e viewpoint of exfoliative cytology. Gastroenterologia Japonica, 4, ) Watanabe, H. (1972) Fibercolonoscopy. Gastroenterologia Japonica, 7, ) Wat anabe, H., Narasaka, T., Uezu fib, J., Miura, K. & Yamagata, S. (1972) An improved ercolonoscope and its application to the colonic diseas es. In: Advances in G astrointestinal Endoscopy, edited by G. Marcozzi and M. Crespi, Piccin Medical Book, P adua and London, pp ;

17 Clinical Observations on Ulcerative Colitis ) Watanabe, H., Narasaka, T. & Yamagata, S. (1975) Studies on the fibercolonoscopy: with special reference to the latest procedures. Tohoku J. exp. Med., 117, ) Yamagata, S., Watanabe, H., Ueno, K. & Yamagishi, G. (1970) Biopsy in the gastrointestinal tract. Gastroenterologia Japonica, 5,