Incidence and Prevalence of Ulcerative Colitis and Crohn's Disease in the County of Copenhagen, 1962 to 1978

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1 GASTROENTEROLOGY 182;83:53-8 and Prevalence of Ulcerative Colitis and Crohn's Disease in the County of Copenhagen, 12 to 178 VIBEKE BINDER, H. BOTH, P. K. HANSEN, C. HENDRIKSEN, S. KREINER and K. TORP-PEDERSEN Medical-Gastroenterological Department C, Herlev Hospital and the Medical-Gastroenterological Department P, Rigshospitalet, University of Copenhagen, Denmark The incidence of ulcerative colitis and of Crohn's disease in the County of Copenhagen was estimated during the years 12 to 178. A total of 0 patients were diagnosed in this area with approximately 500,000 inhabitants. The mean incidence of ulcerative colitis was 8.1 per 5 inhabitants. This incidence was constant during the period for women but rose significantly around 170 for men. The rise in male incidence is due to a rise in the incidence late in life. The prevalence of ulcerative colitis as of December 31,178 was 7 per 5 inhabitants. The incidence of Crohn's disease was increasing during the period for both sexes with a mean value for the period 170 to 178 of 2.7 per 5 inhabitants. The prevalence of Crohn's disease as of December 31, 178 was 34 per 5 inhabitants. Since the cause of chronic inflammatory bowel diseases is still obscure, epidemiologic studies examining differences in occurrence in different places and in different age groups as well as at different times might give a clue as to what factors influence the origin of the diseases. In Denmark the combination of a national health system allowing people to get free medical service independently of their income, a rather stable population, and a well-functioning address registration of the citizens offers suitable conditions for epidemiologic studies. The County of Copenhagen is an area comprising the outskirts of central Copenhagen and with approximately 500,000 inhabitants, well over % of the total Danish population. Received January 2, 182. Accepted April, 182. Address requests for reprints to: Vibeke Binder, M.D., Medical Department C, Herlev Hospital, DK-2730 Herlev, Denmark. This work was supported by the Danish Medical Research Council (Grant No. -080). 182 by the American Gastroenterological Association /82/0053-0$02.50 With a background of operating an outpatient clinic for 20 yr, our aim for the present study was to estimate the annual incidence of ulcerative colitis and Crohn's disease during the 17 yr from 12 to 178. The prevalence of disease at the end of the study (December 31, 178) was also determined. In addition to their etiologic possibilities, these figures offer a planning base for social and medical authorities. Patients and Methods Diagnostic Criteria Since the chronic inflammatory bowel diseases are syndrome diagnoses, the diagnostic criteria used are crucial for the understanding and transferability of the epidemiologic findings. Our diagnostic criteria for ulcerative colitis are in agreement with those from other centers and are based upon the presence of at least three of four criteria: (a) Typical case history with diarrhea or blood and pus, or both, in the stools for more than 1 wk or at repeated episodes. (b) A typical sigmoidoscopic picture with granulated, friable mucosa or ulcerations, or both, of the surface mucosa. (c) Histologic or cytologic signs, or both, of inflammation. (d) Radiologic or colonoscopic signs, or both, of ulcerations with or without spiculated, granulated inner surface of the colon proximal to the rectum. For both ulcerative colitis and Crohn's disease, infectious diseases and neoplastic diseases have to be ruled out beforehand. The diagnosis of Crohn's disease is based upon the presence of at least two offour diagnostic criteria: (a) Case history of diarrhea for more than 3 mo. (b) Radiologic findings with typical stenoses and prestenotic dilatations in the small bowel or segmental findings with copplestone relief in the large bowel. (c) Histologic findings according to Morson (1) with trans-

2 54 BINDER ET AL. GASTROENTEROLOGY Vol. 83, No.3 Table 1. Ulcerative colitis Crohn's disease Patients With Inflammatory Bowel Diseases Living in the County of Copenhagen at Time of Diagnosis Total Number of patients Female Male 31 mural lymphocytic infiltration or occurrence of epithelial granulomas with giant cells of Langhans' type, or both. (d) Occurrence of fistulas or abscesses, or both, in relation to intestinal lesion. Exclusion of infectious diseases was secured by negative stool cultures for 3 consecutive days on specific substrates for Shigella, Salmonella, Staphylococcus and since 17 as well for Yersinia enteracolitica and since 17 for Cambylobacter. The examinations were done in Statens Seruminstitut, the Danish National Institute for microbiology. Microscopic examinations of the stools for 3 consecutive days were carried out for identification of trophozoits, cysts of bowel protozoa, and eggs and larva. In patients having been in endemic areas for Entamoeba histolytica, the rectal mucus was examined immediately after sigmoidoscopy in 37 C saline in a microscope with preheated table. Patients who had antibiotic treatment immediately before the onset of bowel symptoms were not included as patients with ulcerative colitis unless the condition either continued for more than 1 mo after cessation of antibiotics or relapsed after a period free of symptoms, and only if stool cultures did not show any pathogenic microorganism. The recognition of Clostridium dificile as a pathogenic organism in these conditions was not present before 178 but is now routinely tested for in such patients. Background Population The background area is the County of Copenhagen except for a small part on the island of Amager. The area forms a continuous region comprising, in 12, 40,3 inhabitants and, in 178, 573,237 inhabitants. The exact number of persons, grouped by age and sex, living in this area was obtained from the Danish Statistical Department (2) for each of the years 12 to 178. Study Population All patients who fulfilled the diagnostic criteria for either ulcerative colitis or Crahn's disease were living in the Copenhagen County area and had attended an outpatient clinic in one of the hospitals. They were registered according to age, sex, and year of diagnosis. The symptomatologic features and extent of disease at the time of diagnosis was evaluated and a follow-up sheet for each year of observation was worked out. The results of these observations are given separately (3). In addition to these patients who comprised the majority of the total group, patients traced by exploring the records for inflammatory bowel diseases from all other hospitals in the region were included, provided that the diagnostic criteria for inflammatory bowel diseases were fulfilled. Because of the organization of the Danish health care system, it was expected that almost all patients with these diagnoses were diagnosed at the regional hospitals, but to ensure the completeness of the regional group, a questionnaire was also sent to all general practitioners and to the medical, surgical, and pediatric specialists in greater Copenhagen. Eighty percent of the questionnaires were returned and only 8 other patients, or <1%, had to be included into the material. The annual incidence, i.e., the annual number of patients first diagnosed as having ulcerative colitis or Crohn's disease per 0,000 inhabitants, was estimated for each calendar year from 12 to 178. Similarly, the mean incidence was calculated for 5-yr age groups and for men and women separately in relation to the background population of similar age and sex. The prevalence was estimated as the total number of patients with ulcerative colitis or Crahn's disease living in the area per 0,000 inhabitants in the background population. The prevalence was calculated as on December 31, 178, i.e., at the end of the study. Statistics A multiplicative Poisson model with unequal cell rates was used (4) combined with the X Z test. Results The patient group is shown in Table 1. A total of 0 patients were diagnosed as having Crohn's disease or ulcerative colitis during the 17-yr period. The annual incidences of the diseases for each calendar year are shown in Figure 1. The mean per los inhabitants 8 5 Ulcerative colitis Year Figure 1. of ulcerative colitis and Crohn's disease in the County of Copenhagen

3 September 182 INFLAMMATORY BOWEL DISEASE IN COPENHAGEN 55 per 5 inhabitants...'" ~ Ulcerative colitis cf /.-p---<> ~ Crahn's "./ cfdisease o ~ ~ ~ ~ - -,, r r ~ Year Figure 2. of ulcerative colitis and Crohn's disease in the County of Copenhagen in men and women separately. The annual incidences are given as mean of 3 consecutive years. annual incidence for ulcerative colitis for the whole period was 8.1 per 5 inhabitants with no significant change during time. The mean annual incidence for Crohn's disease was 1.8 per 5 inhabitants, but this value has little relevance since the incidence increased significantly during the period. Mean annual incidence between 170 and 178 was 2.7 per 5 inhabitants with a peak incidence in 174 (3.7 per 5 ). The apparent plateau during the following years did not reach statistical significance. The interval between start of symptoms and diagnosis was analyzed, and ranged from 0 to 20 yr with a median of 1.7 yr for ulcerative colitis and 3.2 yr for Crohn's disease. The interval between presenting symptoms and diagnosis did not change during the study period to such an extent that it could explain the increasing number of diagnosed patients. The annual incidence expressed as the mean of 3 consecutive years is shown in Figure 2 for men and women separately. The male incidence of ulcerative colitis increased from the first to the second half of the study period, while the female incidence remained constant. The female to male ratio was 1.5 between 12 and 1 and 1.1 between 170 and 178, which difference is significant (p < 0.01). In Crohn's disease the rise in incidence is parallel in the two sexes. The female to male ratio was 1.5 for the whole period, 1.4 for 12 to 1, and 1.5 for 170 to 178 (NS). The mean annual incidence ( ) calculat- Female Incldence per 5 inhab \ I' I" / I,, I 'I, I I Y, ', JJ I I' \ /\ ' \/ \ I" \...if \ I /, \ / '... \ I / \ \ I /,\ /' 12- I / \ J(--.r / 'V""" ~ / 1/ 1/ 1/ U J < > 70 Age in years Male per 1()5lnhab. per 5 inhabitants ulcerative colitis overall incidence 8.4' Age Crohn's disease overall incidence Figure 3. Mean annual incidence ( ) in different age groups. o ~ ~ - - ~ - - ~ - -,, r r < > 70 Age in years Figure 4. Mean female and male annual incidence in first and second half of the study period in -yr age periods. No significant difference in age of women in the two periods. Significantly higher incidence for men over 0 yr of age in the second half of the study.

4 5 BINDER ET AL. GASTROENTEROLOGY Vol. 83, No. 3 per 5 inhab. Figure 5. of Crohn's disease in different age groups as a mean of the years 12 to 1 and 170 to 178, respectively. The increase is significantly more pronounced in the age between 15 and 35 yr Mean of years Mean of years Age years ed for 5-yr age groups is shown in Figure 3. In ulcerative colitis, the incidence is significantly higher in the age groups yr and in the age group 5-70 yr than in all other age groups. In Crohn's disease, the age groups and yr show a significantly higher incidence than do the others. In Figure 4 the male and female incidence in different age groups is given for the first and the second half of the study period, respectively. The age distribution for women did not differ significantly during the period, while that for men differed significantly with a higher incidence late in life between 170 and 178, which explains the overall rise in male incidence in this period. The age distribution for incidence of Crohn's disease is given in Figure 5 for 12 to 1 and 170 to 178 separately. The rise in incidence is seen in all age groups but is most pronounced between age 15 and 35 yr (X 2 = 7.88, df = 2, P < 0.025). There was no difference between the sexes concerning age distribution. The theory of especially exposed birth cohorts Prevalence per 5 inhab. 178 Prevalence of ulcerative colitis and Crohn's disease Figure. The prevalences for ulcerative colitis 200 and Crohn's disease in different age groups ulcerative colitis overall prevalence Crahn's disease overall prevalence 3205 < ;;, 70, Age in years

5 September 182 INFLAMMATORY BOWEL DISEASE IN COPENHAGEN 57 could not be confirmed since among patients diagnosed in the period 170 to 174 the highest incidence was found in people born between 7 and 7. In the period 174 to 178 the highest incidence was found among people born between and 11. Prevalence At the end of the study, December 31, 178, assessment was made of the total number of patients with ulcerative colitis and Crohn's disease who lived in the Copenhagen County area. This group comprised both patients from the incidence group who stili lived in the area and patients who had moved into the region after their disease had been diagnosed. As well, operated and nonoperated patients were included. The prevalence of ulcerative colitis was 7 per 5 inhabitants and of Crohn's disease 34 per 5 inhabitants. The age distribution of the prevalence group is shown in Figure. The rise in prevalence in ulcerative colitis until the age of 70 yr is as would be expected in a disease starting very often at young age and with a good prognosis. The slight fall in prevalence for persons over 70 yr of age is not explained directly, since the incidence has been constant from the start of this study. A rise in incidence in the 150s has, however, been reported in other countries (5) and could, if present in Denmark as well, explain the lower prevalence in old people. The prevalence figures for different age groups in Crohn's disease is, since the incidence for Crohn's disease has risen during the foregoing 17 yr, only a snapshot of the situation in the region at that time. Discussion The incidence of ulcerative colitis during the 17-yr period was apparently constant, but turned out to be so only in women, while it rose in men, especially in older men. The same diagnostic criteria were used during the total study period, which makes it unlikely that another disease entity, as for instance ischemic colitis, accounts for the additional incidence. The ongoing analysis of the course of the disease in all patients will probably be able to confirm that the disease entity has remained unaltered. In their epidemiologic study from the Oxford area, Evans and Acheson (5) foud.d a similar incidence peak late in life, but in women as well as in men. From Northeast England, Devlin et al. () recently reported a similar age distribution, even if the overall incidence in that region was considerably higher than that in our study. The prevalence is significantly higher than that of only 44 per 5 inhabitants which our group reported yr ago (7). The difference is partly explained by the approximation towards the true value of prevalence with the continuous existence of a specialized outpatient clinic. Improvements in the prognosis of course will also result in a higher prevalence. The observed prevalence is in accordance with what would be expected taking the good prognosis and the ages of the patients at diagnosis into consideration. The findings of an increasing incidence of Crohn's disease are in accordance with figures from Sweden (8,), Scotland (,), Wales (), and England (). In Scotland, Kyle and Stark () recently reported a decline in incidence during 170 to 17 after a significant rise in the foregoing decade. Even if the plateau in incidence for the last 4 yr in the present study did not reach statistical significance, the tendency is obvious and so is the agreement with the Scotch findings. The theory put forward by Hellers () that a specially exposed cohort of patients exists could not be confirmed in our material. The possibility that during the last decade a greater diagnostic ability, especially as to distinguishing patients with Crohn's diseases from patients with ulcerative colitis, should account for the increase in incidence can be excluded, since no simultaneous fall in incidence for ulcerative colitis could be demonstrated. Conclusively, the present findings of a remarkable rise in the incidence of Crohn's disease, which are similar to results from other industrial countries, point to possible environmental factors which in combination with a genetic disposition could be responsible for the outbreak of the disease. Until now, no convincing proposal for such a factor or factors has been given. References 1. Morson BC. Histopathology of Crohn's disease. Proc R Soc Med 18;1: Statistical table works. Copenhagen: Danmarks Statistik Both H, Torp-Pedersen K, Hendriksen C, Binder V. Clinical manifestations of ulcerative colitis and Crohn's disease in a regional patient group. Scand J Gastroenterol182; (in press). 4. Andersen EB. Multiplicative Poisson models with unequal cell rates. Scand J Statist 177;4: Evans JG, Acheson ED. An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut 15;: Devlin HB, Datta D, Dellipiani AW. The incidence and prevalence of inflammatory bowel disease in North Tees health district. World J Surg 180;4: Bonnevie 0, Riis P, Anthonisen P. An epidemiological study of ulcerative colitis in Copenhagen County. Scand J Gastroenterol 18;3: Brahme F. Crohn's disease in a defined population. Gastroenterology 175;: Hellers G. Crohn's disease in Stockholm County Acta Chir Scand 17;(suppl):40.

6 58 BINDER ET AL. GASTROENTEROLOGY Vol. 83, No. 3. Kyle J. An epidemiological study of Crohn's disease in northeast Scotland. Gastroenterology 171;1 : Smith IS, Young S, Gillespie G, et al. Epidemiological aspects of Crohn's disease in Clydesdale Gut 175;1:2-7.. Mayberry J. Rhodes J, Hughes LE. of Crohn's disease in Cardiff between 4 and 177. Gut 17;20: Miller DS, Keighley AC, Langman MJS. Changing patterns in epidemiology of Crohn's disease. Lancet 174;ii:1-3.. Kyle J. Stark G. Fall in the incidence of Crohn's disease. Gut 180;21:340-3.