Mortality in Ulcerative Colitis

Transcription

1 GASTROENTEROLOGY 1982;83:36-43 Mortality in Ulcerative Colitis S. GYDE, P. PRIOR, M. J. DEW, V. SAUNDERS, J. A. H. WATERHOUSE, and R. N. ALLAN Gastroenterology Unit, The General Hospital, Steelhouse Lane, Birmingham, England and The Cancer Epidemiology Unit, University of Birmingham, Birmingham, England The pattern of mortality has been examined in a series of 676 patients with ulcerative colitis under long-term review to identify excesses or deficits in mortality for all causes of death in relation to the general population. The mortality risk for the whole series was 1. 7 times that of the general population (p < 0.001). Most of the excess mortality could be attributed to diseases of the digestive system. There was a heavy burden of mortality during the first year after diagnosis and the first year after radical surgery. The significance of the excess of cancer deaths was due to the inclusion of patients who were diagnosed with cancer at first referral. In men there was a deficit of circulatory system deaths particularly those with early onset ulcerative colitis treated by panproctocolectomy after 40 yr of age. Mortality from all other causes including breast cancer showed no significant difference from that expected in the general population. Various methods have been used to evaluate the mortality in ulcerative colitis. Crude percentage mortality estimates uncorrected for age and unrelated to length of survival are uninformative, and sometimes misleading. Case-control methods were used by Nefzger and Acheson in a large selected series of men admitted to the U. S. Army Hospital in 1944 (1). Several recent studies have assessed total mortality in ulcerative colitis using actuarial methods with or without comparison with the general population. These reports include mortality analyses in clinical series from Oxford (2,3), Leeds (4,5), and Edinburgh (6,7). More recent mortality reports include Devroede et al. (8) who studied childhoodonset colitis in the United States, Bonnevie et al. (9) Received August 18, Accepted ebruary 19, Address requests for reprints to: Dr. R. N. Allan, Gastroenterology Unit, The General Hospital, Steelhouse Lane, Birmingham B4 6NH, England. The authors gratefully acknowledge financial support from the Cancer Research Campaign, and the West Midlands Regional Health Authority by the American Gastroenterological Association /82/ $02.50 who studied a regional cohort of patients in Copenhagen, and Gilat et al. (10) who studied a large series of patients with a relatively short follow-up in Tel Aviv, Israel. inally Storgaard et al. reported a series of 413 patients in Denmark (11). Interseries comparisons of mortality are difficult to make not only because of the different methods used in analysis, but also because of the varying composition in respect of severity of disease in any clinical series. Stratification of patients by age, sex, and extent of disease would go some way to resolving these difficulties, but in most series the subgroups so formed are too small for effective analysis. It is therefore difficult to generalize from the mortality results in any given series. The results do become more meaningful if some comparison is made with the general population. The particular merit of this study is that statistical techniques have been used that allow identification of excesses or deficits in mortality for specified causes of death in relation to the general population. These techniques have been applied to a large group of patients with ulcerative colitis under longterm review drawn from the West Midlands region. Patients and Methods This analysis was based on a consecutive series of 676 patients with ulcerative colitis under review by two consultants (BN Brooke and WT Cooke) between 1940 and The mean follow-up was 15.8 yr. More than 300 of the 676 patients were seen at or near onset of symptoms; the remainder were referred later in the course of their disease. Because the referred cases were included, the bias at entry to the series was inclined towards severe disease in comparison with other reported series as patients were often referred for surgical treatment (Table 1). All but 15 patients were followed up through death or through December 31, 1976 by means of one or more of the following agencies: hospital visit, amily Practitioner, amily Practitioner Committee, National Health Service Central Register, and the Birmingham Regional Cancer Registry. Copies of death certificates were obtained for those patients who had died. In all but 34 cases the current

2 July 1982 MORTALITY IN ULCERATIVE COLITIS 37 Table 1. Proportion of Patients Undergoing Radical Surgery for Ulcerative Colitis Among Reported Hospital Series Number Patients of underpatients going Percent in total radical of total Study series surgery series Nefzger and Acheson (U.S. Army) 1963 (l)a Edwards and Truelove (Oxford) 1964 (2,3) Watts et al. (Leeds) (4,5) Bonnevie (Copenhagen) (9) Present series (Birmingham) a Reference number. status of each patient still alive was ascertained in respect of extent of disease and surgical treatment. The agestructure of the series at diagnosis is shown in igure 1, and the subgrouping of the series by maximum extent of disease and treatment is summarized in Table 2. The series has been analyzed as a whole with patients entered into the analysis from the date of diagnosis of their colitis. The pattern of mortality has been considered in relation to the level of risk over time, age at diagnosis, and to cause of death. The survival experience by each patient was computed from the date of diagnosis through December 31, 1976, or through death if this occurred at an earlier date. An array of patient-years at risk was constructed in terms of sex, age at diagnosis, and years from diagnosis. Age- and sex go Number 80 of patients o ~ ~~~ o go Age in years igure 1. Age distribution at onset and diagnosis in the series of 676 patients with ulcerative colitis. specific mortality rates were computed for all causes of death for the 11 main-group causes as defined by the International Classification of Disease (lcd, 7th Revision) (12). Age-, sex-, and cause-specific rates were computed from mortality and population data for England and Wales, 1961 (Registrar General, 1963) (13), as being a suitable midpoint of the survey period. By applying the rates to the patient-years at risk, the numbers of deaths that might be expected to occur during the period of observation were computed and were compared with the numbers of observed deaths that were also coded by underlying cause to rubrics of the ICD 7th Revision. The level of risk of mortality from all causes of death has also been evaluated in relation to interval from diagnosis and to age at diagnosis. When expressed as "cumulative relative risk" the results are similar in nature to published mortality curves, but are corrected for change in age over the period of observation. The Poisson distribution was used to assess the significance of the differences between observed (0) and expected (E) numbers of deaths. Results Specific Cause of Death Overall main-group causes. The observed and expected number of deaths from all causes and for main-group causes are shown in Table 3. The relative risk of mortality for the whole series was 1.7 times that of the general population (p < 0.001). The relative risk was marginally higher in women (1.9- fold; p < 0.001) than men (1.6-fold; p < 0.001) but the difference was not significant statistically (t = 1.06). Most of the excess mortality in women could be attributed to diseases of the digestive system (group 9). The underlying cause of death was given as ulcerative colitis in 28 cases; the remaining three deaths were from cirrhosis of the liver. The excess death for malignant neoplasms (group 2) was of marginal significance (p < 0.05). The observed num- Table 2. Operation colectomy/ panproctocolectomy Medical treatment All cases Ulcerative Colitis: Distribution by Sex, Extent of Disease, and Operative Procedure Male/female ratio = 1: Extensive Localized colitis disease All cases Sex n % n % n % M M M

3 38 GYDE ET AL. GASTROENTEROLOGY Vol. 83, No.1, Part 1 Table 3. Ulcerative Colitis: Observed and Expected Numbers of Deaths for Main-Group Causes Q lcd Cause of death (7th Rev) Sex Eb OC OlE pd All causes M Group 1: infectious and parasitic diseases M Group 2: malignant neoplasms M < Group 3: allergic and metabolic disorders M Group 4: blood disorders M Group 5: mental and psychotic disease M Group 6: nervous system disorders M Group 7: circulatory system disorders M «0.01) Group 8: respiratory system disorders M (0.05) Group 9: digestive system disorders M Group 10: urinary system disorders M Group 11: accidents, poisoning, and violence E M Remainder M a Analysis from date of diagnosis for 676 patients. be = Expected number. C 0 = Observed number. d Parentheses denote deficit. bers were not significantly different from their expectations for all other causes of death. In particular the observed numbers of deaths attributed to the nervous, circulatory, and respiratory (NCR) systems were in each group very close to the expected numbers. In men the relative risk of mortality attributable to diseases of the digestive system was higher (27.4- fold) than in women, but the difference was not statistically significant. Of the 29 deaths in this group, ulcerative colitis was cited as the underlying cause in 25 cases; the remaining four deaths were due to cirrhosis of the liver, cholangitis, duodenal ulcer, and "colitis." Deaths from malignant neoplasm showed a 1.6-fold increase similar to that in women. In contrast with women, however, there was an apparent deficit of deaths from other causes-12 observed and expected-which was highly significant (p < 0.01). Deaths from diseases of the circulatory and respiratory systems were markedly under-represented. A small deficit in the nervous systems was also observed. In the nervous, circulatory, and respiratory systems overall only seven

4 July 1982 MORTALITY IN ULCERATIVE COLITIS 39 deaths were observed when might have been expected to occur. The lower overall mortality rate in males is a result of this deficit rather than due to a lower mortality rate from ulcerative colitis or cancer. Malignant neoplasm (group 2). The morbidity from cancer in this series has been reported fully elsewhere (15). Only mortality from cancer in the series is considered here (Table 4). In women the excess of cancer deaths was of only borderline significance while in men the excess did not reach the 5% significance level. There was a highly significant excess of deaths from cancer of the digestive organs in both men and women (p < 0.001). The deficit of lung cancer in men was of borderline significance. or all remaining sites, including breast, the numbers of deaths were close to expected numbers. The apparent risk of cancer in any series is biased by the inclusion of those patients in whom late symptomatic cancer was instrumental in initiating their first referral to hospital. Thirteen patients fell into this category, of whom 9 died from cancer of the digestive system and 4 from cancers at other sites. When those deaths were excluded from the analysis, no excess of deaths from cancer overall was recorded (0 = 22: E = 20.87). A small but significant excess of deaths was still present in the digestive system (0 = 14; E = 6.75; OlE = 2.1; P < 0.05) even when these cancers were excluded leaving a deficit at remaining sites (0 = 8; E = 14.12; OlE = 0.6; P = 0.06). Table 4. Cause of death Ulcerative Colitis: Deaths due to Malignant Neoplasrns u ICD (7th Rev) Sex Group 2: malignant M neoplasms Digestive system M Lung M Breast 170 M Reproductive or M urinary systems Remainder M Eb OC OlE < «0.05) a Analysis from date of diagnosis; patients with late cancer included in the analysis. be = Expected number. C 0 = Observed number. d Parentheses denote deficit. Table 5. Age at diagnosis <40 yr 40+ yr Ulcerative Colitis: Nervous, Circulatory, and Respiratory Deaths Categorized by Age at Diagnosis U NCR death~ Sex Eb OC OlE pd M 5.87 «0.01) <0.05 M «0.05) a Analysis from year of diagnosis. be = Expected number. co = Observed number. d Parentheses denote deficit. Nervous, circulatory, and respiratory systems (groups 6, 7, and 8). The deficit of deaths in males for these groups (abbreviated subsequently to NCR deaths) has been examined further. The deaths in these groups are usually considered together because in an analysis using death certificates for cause of death these deaths are considered to be interrelated. The deficit was greater in men whose ulcerative colitis was diagnosed before 40 yr elf age, whereas in women there was a small excess (p < 0.05). After age 40 yr the observed and expected numbers were close in females, but men showed a significant deficit (p < 0.05) (Table 5). The deficit was more apparent in patients undergoing panproctocolectomy than in others (Table 6). urther analysis of the men treated by panproctocolectomy suggested that the deficit was present in all age groups, but that it was at a maximum in those whose disease started before 40 yr of age and who did not undergo surgery until after that age (Table 7). A similar analysis in women showed a small excess of NCR deaths with early onset disease and operation, but in all other groups the observed deaths were close to their expectation. Mortality by Interval from Diagnosis of Ulcerative Colitis When all causes of death were considered in relation to the duration of disease, the highest rela- Table 6. Ulcerative Colitis: Nervous; Circulatory, and Respiratory Deaths Categorized by Treatrnent U NCR deaths Treatment group Sex Eb OC OlE pd All M «0.001) Panproctocolectomy M «0.001) Other M a Analysis from year of diagnosis. be '= Expected number. co = Observed number. d Parentheses denote deficit.

5 40 GYDE ET AL. GASTROENTEROLOGY Vol. 83, No, 1, Part 1 Table 7, Onset <40 < Age (yr) Ulcerative Colitis: Nervous, Circulatory, and Respiratory Deaths by Age at Onset and Age at Panproctocolectornya Operation < Sex M M M NCR deaths o 4 o OlE «0.01) «0.05) I I I I a Analysis from year of diagnosis. be = Expected number. co = Observed number. d Parentheses denote deficit. tive risk of mortality occurred within 5 yr of diagnosis (Table 8). The difference between men and women was not statistically significant (t = 0.98). In men the risk remained elevated and the excess was significant up to 10 yr after diagnosis. After 10 yr, the observed number of deaths in men was close to the expected number (0 = 23; E = 24.34; relative risk = 0.9). In women the observed numbers of deaths were not significantly increased after the first 5 yr from diagnosis, but overall (5+ yr) the excess was just significant (0 = 51; E = 38.56; relative risk = 1.3; P < 0.05). When the results for men and women were combined, the cumulative relative risk showed a marked decline from 4.5. After 5 yr had passed, a very small decrease in cumulative relative risks with time was observed (1.4 to 1.2), but the excess of deaths did not reach statistical significance. Mortality by Age at Diagnosis and Interval from Diagnosis A highly significant excess of deaths was observed in the first year after diagnosis for both men and women under 45 yr of age at diagnosis (Table 9). The risk in years 1-4 was significantly increased in men but not in women. After 5 yr women, but not men, experienced a significantly increased relative risk. Patients whose disease was diagnosed after 45 yr of age also fared badly in the first year, although the relative risks were lower than for the same interval in younger patients. The excess in women was of borderline significance for years i-4, but no further excess was observed in men. E "0 u T-< o 0. ~ V I I I ~ OlNT-<OlOO ~ 0 cr:i~~6~ Q) ~ ""0 Q) ~ Q).n '" o Mortality after Radical Surgery An analysis from the date of operation was carried out for assessing mortality in this group. The results of such an analysis for the 438 patients

6 July 1982 MORTALITY IN ULCERATIVE COLITIS 41 Table 9. Age at diagnosis <45 yr 45+ yr Ulcerative Colitis: Mortality by Age and Interval (All Causes of Death) Interval from diagnosis (yr) Men a E = Expected number. b 0 = Observed number. p Women E o OlE p E o OlE p < <0.05 undergoing major surgery are shown in Table 10. The apparent lack of NCR deaths in men undergoing panproctocolectomy persists. Women again, showed a small but nonsignificant excess of NCR deaths. The relative risk of dying from disorders of the digestive system (group 9) in men was not significantly different from that for women. Of the 44 deaths attributed to group 9, 27 patients (6.4%) died within 1 mo of operation, and another 7 patients (1.6%) died within the first year after surgery (Table 11). The relative risk of dying 12 mo or more after operation was 6.8, the overall risk being 29-fold. All 12 patients who died after colectomy did so within 1 yr of operation. The remaining group of medically treated patients does not constitute a true control group because treatment was not randomly allocated. However, taking the analysis for this group from the date of diagnosis, the 2.1-fold risk of dying from all causes (43/20.34) was not significantly different from the 2.0-fold risk after radical surgery. The risk was fold (16/0.50) when only deaths in the digestive system were considered (group 9) and was no different from that of the radical surgery group after operation. The percentage of deaths in the first year was smaller (2.1 %) but the relative risk of dying after 1 yr or more from diagnosis was higher. Deaths from cancer (group 2) in the operative group were only marginally increased. When the 7 deaths of patients presenting with cancer were excluded, there was no overall excess of cancer deaths (0 = 13; E = 13.53) but 7 of these remaining 13 deaths were attributed to cancers of the digestive system (5 colorectal; 2 hepatobiliary). ive patients with colorectal cancer died at varying intervals from operation, though in 4 patients panproctocolectomy was carried out either for diagnosed or suspected cancer at least 1 yr after first referral to the unit, and Table 10. Ulcerative Colitis: Mortality after Major SurgeryU ICD Treat- Men Women Cause of death (7th Rev) ment b E o OlE pc E o OlE p E o OlE p All causes PPC TC T Group 2: Malignant PPC neoplasms' TC T Groups 6, 7, 8: NCR PPC «0.001) TC T «0.01) Group 9: Digestive system Remainder PPC TC T PPC TC T a or 438 patients; analysis from date of completion of total colectomy. b PPC = panproctocolectomy; TC = total colectomy; T = PPC + TC. C Parentheses denote deficit

7 ~ ~ ~.. ~~ ~ ~ ~o 42 GYDE ET AL. GASTROENTEROLOGY Vol. 83, No.1, Part 1 Table 11. Ulcenitive Colitis: Group 9 Deaths (Digestive System) 0-1 Moo 1-12 Moo Reference No. of No. of No. of 12+ Mo Treatment point patients deaths deaths Eb OC OlE E 0 OlE Radical surgery Operation (6.4%) 7 (1.6%) Medical Diagnosis (0.8%) 3(1.3%) Period from reference point. Mo = Month. be = Expected number. co = Observed number. in the fifth patient a carcinoma developed in the retained rectum after colectomy. In the conservatively treated group,'the risk of cancer was 3.2-fold (15/ 4.76) overall aqd was still 1.9-fold (9/4.76) when those first presenting with cancer were excluded. Among the remaining 9 deaths, 7 were from cancer of the digestive system (4 due to colorectal and 3 to hepatobiliary cancer). Discussion Several factors influence the results of any mortality analysis and complicate comparisons with other series. In,a clinical series some patients are seen near the onset of their disease (primary attack cases) and some are referred later in the course of their disease (referred cases). In this series more than half the cases fell into the "referred" category. Therefore the early mortality may be underestimated in our series. This will to some extent be offset by the high proportion of patients with extensive disease, many of whom were severely ill when referred to the unit for surgical treatment. It is difficult to predict the effect of these factors on the estimated niortality. Nevertheless, the 1.7-fold mortality found in the series was similar to the twofold overall ~isk quoted by Nefzger and Acheson 30 OPERATIONS % 20 MalE!s :!: 2670, I I I I (1), but lower than the threefold risk reported by Storgaard et al. (11). Most of the excess in this series was due to ulcerative colitis or related conditions. The results were similar to other reports that also showed a high risk during the first year after diagnosis of ulcerative colitis and also in the first year after radical surgery. A small excess of deaths from tumors of the digestive system was observed both before and after the exclusion of patients who died from cancer soon after their first referral to the unit. The increased risk of death from tumors of the digestive system in patients undergoing radical surgery is explained in part by the operation being performed after a diagnosis of cancer had been made: that is, the operation was too late to exert any prophylactic effect. Deaths from hepatobiliary carcinoma occurred both in groups who had and who had not undergone surgery, which suggests removal of the colon does not protect against these tumors (14). Elsewhere we have reported a 4.2-fold risk of morbidity from tumors of the digestive system in this series when patients who first presented with cancer were excluded (15). The comparable mortality rate of 2.1-fold suggests that, contrary to an earlier review of the literature (16), a diagnosis of cancer in ulcerative colitis does not always carry a bad prognosis (17,18). The small deficit from cancer of the lung may igure 2. Ulcerative colitis: distribution of operations (panproctocolectomy and total colectomy) by sex and age at operation with mortality rates for disease of the circulatory system (general population) superimposed.

8 July 1982 MORTALITY IN ULCERATIVE COLITIS 43 indicate selection bias in the series, or reflect a reduction in smoking habits or an under-representation of certain socioeconomic classes, and merits further investigation. There was no evidence that deaths from breast cancer were under-represented in the series. As nearly two-thirds of patients underwent panproctocolectomy, it is unlikely that this operation is protective for breast cancer as has been suggested by Goldgraber et al. (19). The observed deficit of deaths from diseases of the nervous, circulatory, and respiratory systems (NCR deaths) could represent selection by virtue of the referral pattern. It is unlikely to be explained by incomplete follow-up since in all but 15 patients the vital status was known. The deficit fell mainly in men treated by panproctocolectomy, being greatest in those with early onset ulcerative colitis but treated by panproctocolectomy after 40 yr of age. This could be explained by selection of late referrals who represent a survivor population from an unknown initial cohort, although the effect was not apparent in women. The differences between men and women may however be explained by the differential mortality rates for circulatory disorders. The distribution of patients undergoing panproctocolectomy or total colectomy by age at operation is shown in igure 2 where mortality rates for disorders of the circulatory system are superimposed. In men the mortality rates increase rapidly over the ages when operations are being carried out, whereas for women the rates do not increase sharply until the operative phase has almost finished. Increasing mortality rates at this time could have the effect of "preselecting" men in the sense that some men might succumb to heart disease at about the age when others return for operation. However, the deficit could represent a real negative association with ulcerative colitis that may be related to weight, smoking, or dietary habits. The association is supported by Nefzger and Acheson (1) who showed a deficit of deaths from coronary artery disease. References 1. Nefzger MD, Acheson ED. Ulcerative colitis in the U.S. Army in Gut 1963;4: Edwards C, Truelove SC. The course and prognosis of ulcerative colitis. Part I and II: short-term and long-term prognosis. Gut 1963;4: Edwards C, Truelove SC. The course and prognosis of ulcerative colitis. Part III and IV: complications and carcinoma of the colon. Gut 1964;5: Watts J McK. dedombal T, Watkinson G, et al. Early course of ulcerative colitis. Gut 1966;7: Watts J McK, dedombal T, Watkinson G, et al. Long-term prognosis of ulcerative colitis. Br Med J 1966;1: Jalan KN, Prescott RJ, Sircus W, et al. An experience of ulcerative colitis. II. Short-term outcome. Gastroenterology 1970;59: Jalan KN, Prescott RJ, Sircus W, et al. An experience of ulcerative colitis. III. Long-term outcome. Gastroenterology 1970;59: Devroede GJ, Taylor W, Sauer WG, et al. Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 1971;285: Bonnevie 0, Binder V, Anthonisen P, et al. The prognosis in ulcerative colitis. Scand J GastroenteroI1974;9: Gilat T, Ribak J, Benaroya Y, et al. Ulcerative colitis in the Jewish Population of Tel-Aviv Yafo. Gastroenterology 1974;66: Storgaard L, Bischoff N, Henriksen E, et al. Survival rates in Crohn's disease and ulcerative colitis. Scand J Gastroenterol 1979;14: World Health Organization. Manual of the International Statistical Classification of Diseases, Injuries and Causes of Death. 7th Revision. Geneva: WHO, Registrar General Statistical Review of England and Wales for the year Part I. London: HMSO, Ritchie JK, Allan RN, Macartney J, et al. Biliary tract carcinoma associated with ulcerative colitis. Q J Med 1974;43: Gyde S, Prior P, Macartney J, et al. Cancer morbidity in ulcerative colitis. Gut 1982;(in press). 16. Slaney G, Brooke BN. Cancer in ulcerative colitis. Lancet 1952;2: Hughes RG, Hall TJ. The prognosis of carcinoma of the colon and rectum complicating ulcerative colitis. Surg Gynecol Obstet 1978;146: Hulten L, Kewenter J, Ahren C, et al. Clinical and morphological characteristics of colitis carcinoma and colorectal carcinoma in young people. Scand J Gastroenterol 1979;14: Goldgraber MB, Humphrey EM, Kirsner JB, et al. Carcinoma and ulcerative colitis: a clinical-pathological study. Gastroenterology 1958;34:840-6.