- Email: [email protected]
Mortality in Ulcerative Colitis: 1930 to 1966
GASTROENTEROLOGY Official Publication of the American Gastroenterological Association C
VOLUME
57
CoPT&IGBT 1969 TBJ> WILLIA.Ke & WtLI
November 1969
NUMBER
5
MORTALITY IN ULCERATIVE COLITIS: 1930 TO 1966 DAviD A. MoRowrrz, M.D., AND JosEPH B. KtRSNER, M.D.
Department of Medicine, University of Chicago, Chicago, Illinois
Causes of death were investigated in 137 ulcerative colitis patients dying between 1930 and 1966. Forty-six patients, averaging 39 years of age, died of causes directly attributable to ulcerative colitis; these included colonic perforation, operative and postoperative deaths, and fulminating disease. The 46 colitis-related deaths were caused by carcinoma of the colon and rectum, chronic liver disease, suicide, phlebothrombosis, and complications of medical therapy. Deaths in 45 patients were unrelated to ulcerative colitis or any of its known complications. Review of the latest barium enema in 125 of the patients under study disclosed a significant correlation between the presence of severely involved colons and direct colitis and colitis-related deaths. The patterns of mortality over the period under study indicate that both the survival times in ulcerative colitis and the ages at death are increasing. Likewise, the major causes of death are changing. There is a decline in the frequency of deaths directly due to ulcerative colitis and a corresponding increase in both colitis-related and colitis-unrelated deaths. Nonetheless, the high over-all proportion (2 of 3) of those patients dying because of factors directly or indirectly related to their bowel disease emphasizes the continuing therapeutic challenge presented by ulcerative colitis. tncerative colitis varies widely in severity from a mild, asymptomatic proctitis to an acute, fulminating, occasionally fatal disease. Although the treatment of this disorder has changed substantially in Received September 20, 1968. Accepted June 12, 1969. This work was presented in part at the 69th Annual Meeting of the American Gastroenterological Association, held in May 1968 in Philadelphia, Pennsylvania. Address requests for reprints to: Dr. David A. Morowitz, Department of Medicine, Malcolm Grow United States Air Force Hospital, Andrews Air Force Base, Washington, D. C. 20331.
recent years, a significant number of patients continue to die because of factors directly or indirectly related to the disease. Edwards and Truelove 1 recently described a cumulative mortality rate of 39.9% in a 23-year study of 624 patients with ulcerative colitis. Nefzger and Acheson 2 found that the 17-year cumulative mortality rate for United States Army personnel with ulcerative colitis (10. 7%) was more than twice that of an age-matched control group (4.8%). Other reportsa-to have indicated rates that differ widely with the time and length of study, as well as with the completeness of pa-
481
482
MOROWITZ AND KIRSNER
tient follow-up. The pertinent mortality statistics of several reviews of the natural history of ulcerative colitis are given m table 1. A systematic study of the causes of death in ulcerative colitis was undertaken in the hope of better understanding the disorder, indicating trends in mortality, and providing guidelines for further decreasing the mortality rate.
Materials and Methods The clinical records of all known deceased ulcerative colitis patients who had been seen at the University of Chicago Gastroenterology Clinic between 1930 and 1966 were reviewed. The diagnosis of ulcerative colitis was made by the usual radiological proctoscopic, and histological criteria. Causes of death were considered established only after an autopsy had been performed, after laboratory studies had been sufficiently completed to justify a final diagnosis, or, in the cases of patients dying elsewhere, after a hospital report or attending physician's statement was so thorough as to leave little doubt as to its validity. Patients with clinical or anatomic features of Crohn's disease of the colon were eliminated from this analysis. Additional data included patient's age at onset of the disease, age at time of death, date of death, duration and course of the illness, radiological extent of the disease, and use of steroids and surgical intervention. Of 162 patients known to have died, data were complete on 137, and 1. Comparison of u lcerative coli tis mortali ty rates as reported in various series f rom 1909 to 1963
T A BLE
Author
Year
-
H awkinsa Hardy and Bulmer' Buzzard et a!. 6 Willard et al. s Wheelock and Warren 7 Banks et aJ.B Cullinan9 Lindner 10 E dwards and Truelove' Nefzge r and Acheson2
-
No. of patients
Follow-up Deaths period
- - - - -- - yr .
%
1909 1933 1938 1938 1955
85 95 116 66 343
18 12 9 12 38
48 33 30 29 54
1957 1957 1960 1963
244 346 391 624
19 8 10 24
20
8 16 40
1963
525
17
11
Vol. 57, No . 5
these form the basis of this study. There were 54 males and 83 females. Causes of death were classified into three groups: (I) direct colitis deaths, (II) colitis-related deaths, and (Ill) colitis-unrelated deaths. Deaths were considered to be directly ascribable to ulcerative colitis if they occurred as a result of the inflammatory process in the colon. Fulminating disease with or without perforation of the bowel and hemorrhage usually characterized this group. Operative and postoperative deaths following colitis surgery also were included. Deaths were considered colitis-related if they resulted from a complication of the chronic course of the disease (i.e. , liver disease or carcinoma of the colon), an untoward result of therapy, or suicide. Fatalities from a variety of illnesses were colitisunrelated.
Results
Direct Colitis Deaths Forty-six deaths were in this category. Autopsies were performed on 33 (72%) patients. Final diagnoses included colonic perforation with peritonitis (16), operative or postoperative deaths (16), fulminating ulcerative colitis without perforation (12), malnutrition (1), and hemorrhage (1). Considerable overlap existed between each of these groups. However, one final diagnosis, considered the primary cause of death, was listed for each patient. The average age of patients in this group was 39 years, and the average duration of disease was 7.4 years. Colonic perforation with peritonitis. Sixteen patients died because of acute colonic perforation with resultant peritonitis. The mean duration of illness was 4.8 years, and the average age at death was 30 years; both figures are significantly lower than those of group I as a whole. Data regarding extent of colon involvement were available on 14 of the 16 patients in this group. In 12 of these, inflammatory changes were present in the entire colon at X-ray or postmortem examination. The remaining 2 had changes that, while severe, were limited to the descending colon. In 13 patients, perforation took place during a period of increased clinical activity of the disease, associated with characteristic bloody di-
November 1969
MORTALITY IN ULCERATIVE COLITIS
arrhea, fever, and abdominal pain. Five patients had coexisting toxic megacolon, and only in 2 did perforations occur during apparent clinical remissions. Five patients succumbed during a "first attack" of the disease, whereas an additional 3 died within 1 year of the onset of illness. Only 4 of the 16 had clinical courses exceeding 10 years in duration. Eight patients died before 1950; corticosteroids or adrenocorticotropin (ACTH) were prescribed in the remaining 8 patients who died after 1950. Operative and postoperative deaths. Sixteen deaths occurred because of complications originating during the operative or postoperative period. Those cases in which the preoperative condition of the patient was such as to suggest that surgery contributed little to the ultimate outcome were omitted. The average age at death was 43 years; the mean duration of illness was 12.9 years. · Fatal postoperative peritonitis occurred in 10 cases. In all, there was no preoperative evidence of bowel perforation, nor was peritonitis noted upon exploration of the abdominal cavity. The resected colon specimens uniformly had been intact. In 7 of the 10 cases, a subtotal colectomy had been performed. At autopsy, anastomotic breakdown was demonstrated in 2 cases, and perforation of a rectal stump was noted once. Intra-abdominal infection and death followed elective resection of a sigmoid mucus fistula; 1 patient dying with peritonitis was found at autopsy to have an acute bacterial endocarditis superimposed upon a deformed aortic valve. In the 3 cases complicated by peritonitis following total colectomy, there was one instance of retraction of the ileostomy stump into the abdomen. In two instances, contamination of the abdomen could not be readily explained but probably resulted from unidentified preoperative perforations of the colon. Of 6 postoperative deaths without peritonitis, 2 . were due to cerebrovascular accidents; 2 were attributed to pulmonary infection; and 1 was caused by a myocardial infarction. One death was unexplained.
483
Total involvement of the colon was seen in 5 of the 10 patients dying with peritonitis, and in another 5, inflammatory changes, although severe, were seen in ·less than 50% of the length of the resected specimen. Eight patients were operated on under what were interpreted as emergency circumstances, and of these, 3 had preoperative evidence of megacolon. Fulminating ulcerative colitis. "Fulminating ulcerative colitis" without colonic perforation or · massive hemorrhage was the cause of death in 12 patients averaging 50 years of age. Final diagnoses included malnutrition (3), electrolyte imbalance (2), "intractable diarrhea" (2), and septicemia (5). Autopsies were performed on 7 of the 12 patients, all of whom were found to have severe and total involvement of the colon. Cytomegalic inclusion disease was discovered postmortem in 2 instances. Of the 5 patients on whom autopsy was not performed, 3 had extensive colitis by radiological criteria; 2 patients had not undergone X-ray studies prior to death. There were no cases of toxic megacolon in this group. The mean duration of illness was only 3.3 years; 6 patients died having had ulcerative colitis for 1 year or less. Five patients died prior to 1950; steroids or ACTH was prescribed for 6 of the remaining 7. Hemorrhage and malnutrition. Only one death in the entire series could be attributed to exsanguinating hemorrhage from the colon. In this case, severe bleeding had gone untreated at home, and death occurred upon arrival in the hospital. Nonetheless, severe colonic bleeding was important insofar as it led to operative deaths, transfusion reactions, and the development of fatal postransfusion hepatitis. Another patient probably died from profound malnutrition after protracted illness.
Colitis-related Deaths A total of 46 patients fell into this group with autopsy data or histological confirmation of final diagnosis available on 35 (71 %) of these. Each of the diag-
484
MOROWITZ AND KIRSNER
noses represented a known major complication of chronic ulcerative colitis or of its medical or surgical therapy. The average age at time of death was 36 years, with an average duration of illness of 11.7 years. Carcinoma of the colon. Carcinoma of the colon and rectum with metastases accounted for 16 deaths in patients ranging in age from 21 to 74 years, with a mean of 38 years, Only 1 patient had had ulcerative colitis for less than 10 years, and he, coincidentally, was the oldest of the group. Eleven patients had colitis for 15 years or longer, and 7 patients had this diagnosis for more than one-half of their lifetime. The average duration of illness prior to time of death was 17.3 years. Review of X-rays or pathology reports revealed that 14 of the 16 patients with carcinoma had total involvement of the colon by the primary process. In the remaining 2, only the descending colon was involved, but both patients had had colitis for 23 years. Multiple colonic malignancies were observed in 2 patients; each had three primary lesions. The chronological distribution of deaths from colon carcinoma was of interest. Only two were recorded between 1930 and 1950, and, despite the growth of the colitis population here, there was no corresponding increase in carcinoma deaths in the 1960's. Nine deaths took place between 1950 and 1959, representing a transient increase in frequency. The reason for this unusual distribution is unclear, but increasing awareness of this complication and early surgical treatment probably have been important in the lower incidence of carcinoma deaths recently. Suicide. Since 6 patients' deaths were attributed to suicide, it represents a major source of mortality in this series. A common feature of these patients was their relative youth; 5 of the 6 were under 30 years of age; the oldest was 34. Three had been treated by psychiatrists for depressive reactions, while 2 others gave no prior indication of serious psychiatric disturbances. One patient, regarded as schizophrenic, committed suicide 2 years following a total colectomy
Vol. 57, No. 5
and ileostomy. The average age at death was 26.5 years; the mean duration of disease was 7.3 years and ranged from 8 months in 1 patient to 15 years in another. We recorded no suicides in ulcerative colitis prior to 1951. Although 3 patients were receiving corticosteroids at the time of death, no clear relation between the administration of these drugs and the onset of psychiatric symptoms could be established. Chronic liver disease. Five patients, 2 females and 3 males, died because of chronic liver disease that could not be related to any previous history of viral hepatitis, contact with hepatotoxic agents, or alcoholism. It was assumed that ulcerative colitis played a primary role in the liver disease in each of the 5 patients. All expired after 1953, having had ulcerative colitis for an average of 9.8 years. The mean age at death was 30 years. Three patients died from bleeding esophageal varices, 1 immediately following a splenectomy and a splenorenal shunt. Two died in hepatic failure. Autopsies were performed in all 5 patients. The final microscopic diagnoses included biliary cirrhosis in 3 cases, portal cirrhosis in 1, and active hepatitis with cirrhosis in 1. One patient was found at autopsy to have a localized cholangiocarcinoma. The colitis per se appeared less severe than in patients dying of cancer or of causes directly referable to ulcerative colitis. The patient records gave the impression that the liver disease largely dominated the clinical picture in each case. Review of X-rays and surgical pathology reports disclosed colon involvement to be severe in 2 cases, moderate in 2, and mild in 1. Phlebothrombosis. Several observations have been made regarding the association of venous thrombosis and ulcerative colitis. Three patients in the present series died because of complications of thrombophlebitis or its therapy. One patient developed an iliofemoral and vena caval thrombosis and died of a subarachnoid hemorrhage while being anticoagulated. There were 2 cases of fatal pul-
November 1969
MORTALITY IN ULCERATIVE COLITIS
monary embolism. As might be expected, patients dying with this complication were older than the majority of the group. The patient with the vena cava thrombosis was 37 years old at the time of death; the remaining 2 were 63 and 71 years of age, respectively. Additional complications of chronic ulcerative colitis were implicated as causes of death in 2 patients. One patient died of renal amyloidosis at the age of 16 after a 6-yeal' history of colitis. Pyoderma gangrenosum with confluent necrosis of large areas of the skin resulted in the death of a 59-year-old woman who had had ulcerative colitis for 12 years. Complications of therapy. A total of 14 patients died because of side effects of therapy rather than the disease itself. The use of blood and blood products indirectly accounted for 7 of these deaths. The final diagnoses included transfusion incompatibility reactions (3), fulminating serum hepatitis (2), and congestive heart failure due to overtransfusion (2). All of the fatalities occurred after 1949. Adverse reactions to drugs were implicated in three deaths. Steroids probably were instrumental in 1 instance of acute fatal upper gastrointestinal hemorrhage with ulceration and in 1 case of duodenal ulcer perforation. In both patients, there had been no history of acid-peptic disease prior to the use of steroids. The drugs were not employed as emergency measures, and the ulcerations did not occur as terminal events of a fulminating ulcerative colitis. One instance of renal failure was reported secondf}ry to renal tubular crystallization of sulfadiazine. Inadvertent trauma to the femoral artery in an attempted venipuncture resulted in a fatal iliofemoral arterial thrombosis in 1 case. Late complications of colon surgery resulted in 2 deaths (peritoneal adhesions and ileostomy stenosis).
Deaths Unrelated to Ulcerative Colitis Forty-five patients with ulcerative colitis, averaging 54 years of age, died for reasons apparently unrelated to the in-
485
testinal disease. Autopsies were performed on 35 (78%). Causes of death included myocardial infarction (14), cerebrovascular accidents (8), non-colonic malignancies (7), congestive heart failure (3), pneumonia (3), suppurative cholangitis (3), traumatic esophageal perforation (1), pulmonary fibrosis (1), chronic renal disease (1), and emphysema (1). There were three accidental deaths in this group. The average duration of ulcerative colitis in these patients was 12.0 years. Radiological Observations In an attempt to find a relationship between the extent of colon involvement and the ultimate cause of death, the latest barium examinations of the colon were reviewed in 105 of the 127 deceased patients. In another 17, only the radiologist's report was available, and 12 patients had no record of a barium enema. The radiological appearance of the colitis was graded as severe, moderate, or minimal, depending largely upon the extent of colon involvement. Inflammatory involvement of more than two-thirds of the length of the colon was arbitrarily graded severe, while minimal involvement implied that the barium examination was either normal or that inflammatory changes were limited to the rectum or rectosigmoid. Distribution of patients according to extent of disease is compared with the final diagnostic category in table 2. As in 2. Distribution of final diagnoses compared with degree of involvement of the colon on barium enema
T A BLE
486
MOROWITZ AND KIRSNER
prior reports, 11 ' 12 a striking relationship is seen between the occurrence of direct colitis and colitis-related deaths and the presence of severe involvement of the colon as seen upon X-ray. Of the 83 patients whose disease involved more than two-thirds of the colon, 70 died of causes either directly due to, or related to ulcerative colitis; only 13 deaths in patients with severe colitis were unrelated to their bowel disease. Conversely, 18 of 24 patients with minimal involvement died of causes unrelated to colitis. Thirty-six of the 42 direct colitis deaths (86%) occurred in patients with X-ray evidence of severe disease; a similar proportion was noted (79%) in patients whose deaths were colitis-related. On the other hand, in those with colitis-unrelated deaths, 18 of 40 colon X-rays (45%) showed minimal involvement, while only 13 (33%) were judged severe.
Chronological Observations Duration of disease. The average duration of disease prior to death appears to be increasing slightly for all patients (fig. 1) . Between 1930 and 1939, the over-all mean duration of illness wa!l 3.8 years, whereas between 1960 and 1966, it had increased to 14.4 years. However, a total
Vol . 57, No. b
of 25 patients died within 1 year of the onset of their illness, and only 7 patients were known to have had ulcerative colitis for more than 30 years. Age at death. The average age at time of death for all patients was only 43 years, but this also seems to be increasing with passage of time (fig. 2). Between 1930 and 1939, the mean age at death was 37 years, while between 1960 and 1966, it was 48 years. The distribution of all patients according to age at death is illustrated in figure 3. Ages at death ranged from 6 to 86 years. Interestingly, patients dying because of factors related to ulcerative colitis (group II) were younger (36 years) than those succumbing as a direct consequence of the bowel disease (group I). However, the group II patients usually had their disease for a longer period of time (11.7 years, compared with 7.4 years). The relatively low average age at death (54 years) of patients dying of factors apparently unrelated to ulcerative colitis raises several interesting speculations. The first, of course, is that the chronic bowel disease represents a damaging influence, in some unknown manner rendering the patient more susceptible to the development of degenerative disease or
- 15
15
Ul
a::
UJ
>-
z
10
UJ
-
10
Ul
UJ Ul
0
u. 0
z
0
5
5
~
a:: => 0
0
1930 · 34 1935-39
1940-44 1945-49 1950 -54 1955-59 1960-66
0
DATES OF DEATH
FIG. 1. Average duration of ulcerative colitis in deceased patients from 1930 to 1966.
November 1969
487
MORTALITY IN ULCERATIVE COLITIS 50
40 (/)
a: <[
w >-
30
~
w
20
~
<[
10
1930-39
1940-49
1950-59
1960-66
FIG. 2. Average age at time of death in all patients from 1930 to 1966. 30
25 (/)
,.._
z
w
20
;::
... 0 0:
15
w
(I)
::<
10
:::>
z
AGE- YEARS
FIG. 3. Distribution of all patients according to age at death.
noncolonic malignancy. Another possibility is that deaths from vascular occlusion may represent manifestations of enhanced intravascular clotting known to be associated with ulcerative colitis. While the average age at death of patients dying of myocardial infarctions was 67 years, the average age of those dying with cerebrovascular accidents was only 52 years. Number and distribution of deaths. This study includes only 34 deaths between 1930 and 1949; however, 103 deaths occurring between 1950 and 1966 are listed. Inasmuch as the survival time appears to be increasing, the increasing number of deaths over the years (fig. 4A) in part reflects the growth of the Gastro-
enterology Clinic at the University of Chicago (fig. 4B). Defining a true death rate from these figures is difficult, inasmuch as the total clinic population is uncontrolled and always fluctuating. As in prior reports, the majority of deaths occurring because of colitis took place in the first few years after the onset of clinical disease. This distribution is illustrated in figure 5. Of the 46 direct colitis deaths, 18 occurred within 1 year after diagnosis, and an additional 7 took place within 5 years. Although the colitis-related deaths were distributed more evenly over the study period, they also tended to cluster in the first years of disease. This probably reflected the early
488
MOROWITZ AND KIRSNER
incidence of suicide and complications of therapy. The carcinoma deaths accounted for a majority of the colitis-related deaths occurring between 10 and 20 years after diagnosis. The distribution of deaths during various therapeutic eras was compared to determine possible differences in mortality patterns (table 3). The period under study was separated, at 1950, into presteroid and steroid eras. The presteroid era was further divided into the period from 1930 to 1938, when antibacterials were not available, and from 1939 to 1949 when they were available. Between 1950 and 50
Vol. 57, No. 5
1966, 72 of 103 deceased patients received ACTH or steroids, and 31 did not. In the presteroid era, direct colitis deaths comprised 21 of a total of 34 deaths or 62%. Since 1950, the proportion has fallen to 24%, or 25 of 103 fatalities. A corresponding increase, however, is noted in the proportion of colitis-related deaths. For example, in the presteroid era, there were 7 colitis-related deaths among 34 patients or 21%. In the steroid era, this figure has risen to 38% or 39 of 103 patients. Extending these observations to the major final diagnoses themselves and again comparing the eras before and after
A
40 (/)
J: ~
<1:
w
30
0
~
z
w
20
~
<1:
Cl.
10
0
J 1930·34
193~ · 39
1940·44
194~·49
19~0-~4
19~~- ~9
1960·66
YEAR 1000
B
900 (/) ~
800
w
700
z
~
<1:
Cl.
~ ~
600 500
_J
0 u
400
~
300
z
200
w 100 0 1930·34 1935 · 39
1940·44 1945·49 1950· 54 1955-59 1960·66
YEAR FIG. 4. A, chronological distribution of ulcerative colitis patient deaths at the University of Chicago Clinic. B , growth of the ulcerative colitis population at the University of Chicago between 1930 and 1966.
November 1969
489
MORTALITY IN ULCERATIVE COLITIS
! :~ ll.. . .C OL~ .~S DE.:.H.S~- ~·- · L_~-~ - - - - - L-~- - L- ..
~
~z
::>
1:
~
.. - -
COLITIS RELATE D DEATHS
oJ •1- I
P
"
COLITIS U,.RELATEO DEATHS 7
I
5
' 20
10
.
25
- .... .30
35
YEAR OF ILLNESS
FIG. 5. Distribution of deaths in all ulcerative colitis patients according to year of illness.
1950 (table 4), we note that colon perforation accounted for 24% of the deaths before 1950 and 8% after; fulminating ulcerative colitis caused 15% of the deaths prior to 1950 and 7% after. The incidence of operative and postoperative deaths and mortality due to complications of medical treatment have remained essentially unchanged since 1950, but the incidence of carcinoma of the colon and rectum, chronic liver disease, suicide, and all colitis-related deaths has increased significantly. Likewise, the frequency of colitis-unrelated deaths has risen from 21 to 37%, reflecting in part the longer life of these patients. The increases in longevity and the changes in mortality patterns since 1950 appear to relate, at least in part, to the increasing use of ACTH and 3. Distribution of deaths in ulcerative colitis patients according to various therapeutic eras
T ABLE
No. of deaths Era Colitisdirect
Colitis- ~ related
Colitisunrelated
----- - - - - -- ·
Presteroid e ra (34 patients)
1930- 1938 1939- 1949 Steroid era tients)
I
4
1
17
6
4
2
4
9
21
30
18 21
(103 pa-
1950-1966 No steroids Steroids use d
4. Comparison of the incidence of the major final diagnoses in ulcerative colitis before and after 1950
TABLE
Cause of death
Incidence
I
1 193o-1949
- -- -- - -- - ·
Colon perforation Fulminating ulcerative colitis Operative -postoperat ive Carcinoma, colon and rectum Chronic liver disease Suicide Complications of medical t herapy Coli t is-un related deaths
195o-1966
· ---
%
%.
24
8 7 12 14 5 6
15 12 6 0 0 12 21
10
37
corticosteroids. 13 - 15 Nonetheless, experience in the choice and timing of surgery, increasing awareness of the major complications of colitis, and availability of antibiotics effective against gram-negative bacteria also have been important.
Discussion Although the patients described in this series provide useful information on the causes of death in ulcerative colitis and the trends from 1930 to 1966, the conclusions to be drawn with regard to the colitis population as a whole are limited for several reasons. First, the severity of the ulcerative colitis referred to the University of Chicago Clinic probably is greater than generally prevails. Second, the pa-
490
MOROWITZ AND KIRSNER
tients lost to follow-up probably can be assumed to have had milder forms of illness and, therefore, be less likely to die of ulcerative colitis or its complications. Similarly, we were more likely to learn of colitis or colitis-related deaths occurring elsewhere in our patients than of colitisunrelated deaths. Despite these factors, the statistics derived from this analysis are disturbing. The average age at death for all deceased patients was only 43 years, and the average duration of illness was 10.7 years. Even in those individuals in whom ulcerative colitis could not be implicated in the final cause of death, the average age at death was only 54 years. These data, and similar experiences in the literature, appear to indicate that the development of ulcerative colitis is a health-threatening and life-shortening event of significant proportions, particularly when inflammatory changes in the colon are extensive. The problems associated with ulcerative colitis, and probably with the other forms of inflammatory bowel disease, clearly are not limited to the bowel but involve every bodily system and structure. Comprehensive studies involving all clinical and investigative approaches, therefore, seem necessary in the further investigation of this complex disease. REFERENCES 1. Edwards, F . C. , and S . C. Truelove. 1963. The course and prognosis of ulcerative colitis. II. Long-term prognosis. Gut 4: 309-315. 2. Nefzger, M. D., and E . D. Acheson. 1963. Ulcerative colitis in the United States Army in 1944. Gut 4: 183-192. 3. Hawkins, H. D. 1909. Natural history of ulcerative colitis and its bearing on treatment. Brit. Med . J . 1: 765-770.
Vol . 57, No. 5
4. Hardy, T. L., and E. Bulmer. 1933. Ulcerative colitis: a survey of ninety-five cases. Brit. Med . J . 2: 812- 815. 5. Buzzard, E . M., J. S. Richardson, and R. W. D. Turner. 1938. Ulcerative colitis: the outlook for the patient. St. Thomas Hosp. Rep. 3: 55..:.67. 6. Willard, J. H., J . F. Pessel, J . W. Hundley, and H . L. Bockus. 1938. Prognosis of ulcerative colitis. J . A.M. A . 111: 2078-2084. 7. Wheelock, F. C., and R. Warren. 1955. Ulcerative colitis: follow-up ~tudies. New Eng. J. Med. 252: 421-25. 8. Banks, B. M ., B. I. Korelitz, and L. Zetzel. 1957. The course of non-specific ulcerative colitis: review of twenty years' experience and late results. Gastroenterology 32: 983-1012. 9. Cullinan, E. R., and I. P . MacDougall. 1957. The natural history of ulcerative colitis. Lancet 1: 487-489. 10. Lindner, A. E ., R. C. King, and R. J . Bolt. 1960. Chronic ulcerative colitis. A clinical appraisal and follow-up study. Gastroenterology 39: 153-160. 11. Bockus, H. L., J . L. A. Roth, E. Buchman, M. Kalger, W. R. Staub, A. Finkelstein, and A. Valdes-Dapena. 1956. Life history of nonspecific ulcerative colitis: relation of prognosis to anatomical and clinical varieties. Gastroenterologia (Base[) 86: 549-581. 12. Watts, J., F. T . de Dombal, G. Watkinson, and J. C. Goligher. 1966. Long term prognosis of ulcerative colitis. Brit. Med. J . 1: 1447- 1453. 13. Truelove, S. C., and L. J . Witts. 1955. Cortisone in ulcerative colitis. Final report on a therapeutic trial. Brit. Med . J. 2: 1041-1048. 14. Spencer, J. A., J. B. Kirsner, P. Mlynaryk, P. I. Reed, and W. L. Palmer. 1962. hnmediate and prolonged therapeutic effects of corticotrophin and adrenal steroids in ulcerative colitis. Observations in 340 cases for periods up to ten years. Gastroenterology 42: 113-129. 15. Korelitz, B. I. , and A. E. Lindner. 1964. The influence of corticotrophin and adrenal steroids on the course of ulcerative colitis: a .comparison with the presteroid era. Gastroenterology 46: 671-679.
VOLUME
57
CoPT&IGBT 1969 TBJ> WILLIA.Ke & WtLI
November 1969
NUMBER
5
MORTALITY IN ULCERATIVE COLITIS: 1930 TO 1966 DAviD A. MoRowrrz, M.D., AND JosEPH B. KtRSNER, M.D.
Department of Medicine, University of Chicago, Chicago, Illinois
Causes of death were investigated in 137 ulcerative colitis patients dying between 1930 and 1966. Forty-six patients, averaging 39 years of age, died of causes directly attributable to ulcerative colitis; these included colonic perforation, operative and postoperative deaths, and fulminating disease. The 46 colitis-related deaths were caused by carcinoma of the colon and rectum, chronic liver disease, suicide, phlebothrombosis, and complications of medical therapy. Deaths in 45 patients were unrelated to ulcerative colitis or any of its known complications. Review of the latest barium enema in 125 of the patients under study disclosed a significant correlation between the presence of severely involved colons and direct colitis and colitis-related deaths. The patterns of mortality over the period under study indicate that both the survival times in ulcerative colitis and the ages at death are increasing. Likewise, the major causes of death are changing. There is a decline in the frequency of deaths directly due to ulcerative colitis and a corresponding increase in both colitis-related and colitis-unrelated deaths. Nonetheless, the high over-all proportion (2 of 3) of those patients dying because of factors directly or indirectly related to their bowel disease emphasizes the continuing therapeutic challenge presented by ulcerative colitis. tncerative colitis varies widely in severity from a mild, asymptomatic proctitis to an acute, fulminating, occasionally fatal disease. Although the treatment of this disorder has changed substantially in Received September 20, 1968. Accepted June 12, 1969. This work was presented in part at the 69th Annual Meeting of the American Gastroenterological Association, held in May 1968 in Philadelphia, Pennsylvania. Address requests for reprints to: Dr. David A. Morowitz, Department of Medicine, Malcolm Grow United States Air Force Hospital, Andrews Air Force Base, Washington, D. C. 20331.
recent years, a significant number of patients continue to die because of factors directly or indirectly related to the disease. Edwards and Truelove 1 recently described a cumulative mortality rate of 39.9% in a 23-year study of 624 patients with ulcerative colitis. Nefzger and Acheson 2 found that the 17-year cumulative mortality rate for United States Army personnel with ulcerative colitis (10. 7%) was more than twice that of an age-matched control group (4.8%). Other reportsa-to have indicated rates that differ widely with the time and length of study, as well as with the completeness of pa-
481
482
MOROWITZ AND KIRSNER
tient follow-up. The pertinent mortality statistics of several reviews of the natural history of ulcerative colitis are given m table 1. A systematic study of the causes of death in ulcerative colitis was undertaken in the hope of better understanding the disorder, indicating trends in mortality, and providing guidelines for further decreasing the mortality rate.
Materials and Methods The clinical records of all known deceased ulcerative colitis patients who had been seen at the University of Chicago Gastroenterology Clinic between 1930 and 1966 were reviewed. The diagnosis of ulcerative colitis was made by the usual radiological proctoscopic, and histological criteria. Causes of death were considered established only after an autopsy had been performed, after laboratory studies had been sufficiently completed to justify a final diagnosis, or, in the cases of patients dying elsewhere, after a hospital report or attending physician's statement was so thorough as to leave little doubt as to its validity. Patients with clinical or anatomic features of Crohn's disease of the colon were eliminated from this analysis. Additional data included patient's age at onset of the disease, age at time of death, date of death, duration and course of the illness, radiological extent of the disease, and use of steroids and surgical intervention. Of 162 patients known to have died, data were complete on 137, and 1. Comparison of u lcerative coli tis mortali ty rates as reported in various series f rom 1909 to 1963
T A BLE
Author
Year
-
H awkinsa Hardy and Bulmer' Buzzard et a!. 6 Willard et al. s Wheelock and Warren 7 Banks et aJ.B Cullinan9 Lindner 10 E dwards and Truelove' Nefzge r and Acheson2
-
No. of patients
Follow-up Deaths period
- - - - -- - yr .
%
1909 1933 1938 1938 1955
85 95 116 66 343
18 12 9 12 38
48 33 30 29 54
1957 1957 1960 1963
244 346 391 624
19 8 10 24
20
8 16 40
1963
525
17
11
Vol. 57, No . 5
these form the basis of this study. There were 54 males and 83 females. Causes of death were classified into three groups: (I) direct colitis deaths, (II) colitis-related deaths, and (Ill) colitis-unrelated deaths. Deaths were considered to be directly ascribable to ulcerative colitis if they occurred as a result of the inflammatory process in the colon. Fulminating disease with or without perforation of the bowel and hemorrhage usually characterized this group. Operative and postoperative deaths following colitis surgery also were included. Deaths were considered colitis-related if they resulted from a complication of the chronic course of the disease (i.e. , liver disease or carcinoma of the colon), an untoward result of therapy, or suicide. Fatalities from a variety of illnesses were colitisunrelated.
Results
Direct Colitis Deaths Forty-six deaths were in this category. Autopsies were performed on 33 (72%) patients. Final diagnoses included colonic perforation with peritonitis (16), operative or postoperative deaths (16), fulminating ulcerative colitis without perforation (12), malnutrition (1), and hemorrhage (1). Considerable overlap existed between each of these groups. However, one final diagnosis, considered the primary cause of death, was listed for each patient. The average age of patients in this group was 39 years, and the average duration of disease was 7.4 years. Colonic perforation with peritonitis. Sixteen patients died because of acute colonic perforation with resultant peritonitis. The mean duration of illness was 4.8 years, and the average age at death was 30 years; both figures are significantly lower than those of group I as a whole. Data regarding extent of colon involvement were available on 14 of the 16 patients in this group. In 12 of these, inflammatory changes were present in the entire colon at X-ray or postmortem examination. The remaining 2 had changes that, while severe, were limited to the descending colon. In 13 patients, perforation took place during a period of increased clinical activity of the disease, associated with characteristic bloody di-
November 1969
MORTALITY IN ULCERATIVE COLITIS
arrhea, fever, and abdominal pain. Five patients had coexisting toxic megacolon, and only in 2 did perforations occur during apparent clinical remissions. Five patients succumbed during a "first attack" of the disease, whereas an additional 3 died within 1 year of the onset of illness. Only 4 of the 16 had clinical courses exceeding 10 years in duration. Eight patients died before 1950; corticosteroids or adrenocorticotropin (ACTH) were prescribed in the remaining 8 patients who died after 1950. Operative and postoperative deaths. Sixteen deaths occurred because of complications originating during the operative or postoperative period. Those cases in which the preoperative condition of the patient was such as to suggest that surgery contributed little to the ultimate outcome were omitted. The average age at death was 43 years; the mean duration of illness was 12.9 years. · Fatal postoperative peritonitis occurred in 10 cases. In all, there was no preoperative evidence of bowel perforation, nor was peritonitis noted upon exploration of the abdominal cavity. The resected colon specimens uniformly had been intact. In 7 of the 10 cases, a subtotal colectomy had been performed. At autopsy, anastomotic breakdown was demonstrated in 2 cases, and perforation of a rectal stump was noted once. Intra-abdominal infection and death followed elective resection of a sigmoid mucus fistula; 1 patient dying with peritonitis was found at autopsy to have an acute bacterial endocarditis superimposed upon a deformed aortic valve. In the 3 cases complicated by peritonitis following total colectomy, there was one instance of retraction of the ileostomy stump into the abdomen. In two instances, contamination of the abdomen could not be readily explained but probably resulted from unidentified preoperative perforations of the colon. Of 6 postoperative deaths without peritonitis, 2 . were due to cerebrovascular accidents; 2 were attributed to pulmonary infection; and 1 was caused by a myocardial infarction. One death was unexplained.
483
Total involvement of the colon was seen in 5 of the 10 patients dying with peritonitis, and in another 5, inflammatory changes, although severe, were seen in ·less than 50% of the length of the resected specimen. Eight patients were operated on under what were interpreted as emergency circumstances, and of these, 3 had preoperative evidence of megacolon. Fulminating ulcerative colitis. "Fulminating ulcerative colitis" without colonic perforation or · massive hemorrhage was the cause of death in 12 patients averaging 50 years of age. Final diagnoses included malnutrition (3), electrolyte imbalance (2), "intractable diarrhea" (2), and septicemia (5). Autopsies were performed on 7 of the 12 patients, all of whom were found to have severe and total involvement of the colon. Cytomegalic inclusion disease was discovered postmortem in 2 instances. Of the 5 patients on whom autopsy was not performed, 3 had extensive colitis by radiological criteria; 2 patients had not undergone X-ray studies prior to death. There were no cases of toxic megacolon in this group. The mean duration of illness was only 3.3 years; 6 patients died having had ulcerative colitis for 1 year or less. Five patients died prior to 1950; steroids or ACTH was prescribed for 6 of the remaining 7. Hemorrhage and malnutrition. Only one death in the entire series could be attributed to exsanguinating hemorrhage from the colon. In this case, severe bleeding had gone untreated at home, and death occurred upon arrival in the hospital. Nonetheless, severe colonic bleeding was important insofar as it led to operative deaths, transfusion reactions, and the development of fatal postransfusion hepatitis. Another patient probably died from profound malnutrition after protracted illness.
Colitis-related Deaths A total of 46 patients fell into this group with autopsy data or histological confirmation of final diagnosis available on 35 (71 %) of these. Each of the diag-
484
MOROWITZ AND KIRSNER
noses represented a known major complication of chronic ulcerative colitis or of its medical or surgical therapy. The average age at time of death was 36 years, with an average duration of illness of 11.7 years. Carcinoma of the colon. Carcinoma of the colon and rectum with metastases accounted for 16 deaths in patients ranging in age from 21 to 74 years, with a mean of 38 years, Only 1 patient had had ulcerative colitis for less than 10 years, and he, coincidentally, was the oldest of the group. Eleven patients had colitis for 15 years or longer, and 7 patients had this diagnosis for more than one-half of their lifetime. The average duration of illness prior to time of death was 17.3 years. Review of X-rays or pathology reports revealed that 14 of the 16 patients with carcinoma had total involvement of the colon by the primary process. In the remaining 2, only the descending colon was involved, but both patients had had colitis for 23 years. Multiple colonic malignancies were observed in 2 patients; each had three primary lesions. The chronological distribution of deaths from colon carcinoma was of interest. Only two were recorded between 1930 and 1950, and, despite the growth of the colitis population here, there was no corresponding increase in carcinoma deaths in the 1960's. Nine deaths took place between 1950 and 1959, representing a transient increase in frequency. The reason for this unusual distribution is unclear, but increasing awareness of this complication and early surgical treatment probably have been important in the lower incidence of carcinoma deaths recently. Suicide. Since 6 patients' deaths were attributed to suicide, it represents a major source of mortality in this series. A common feature of these patients was their relative youth; 5 of the 6 were under 30 years of age; the oldest was 34. Three had been treated by psychiatrists for depressive reactions, while 2 others gave no prior indication of serious psychiatric disturbances. One patient, regarded as schizophrenic, committed suicide 2 years following a total colectomy
Vol. 57, No. 5
and ileostomy. The average age at death was 26.5 years; the mean duration of disease was 7.3 years and ranged from 8 months in 1 patient to 15 years in another. We recorded no suicides in ulcerative colitis prior to 1951. Although 3 patients were receiving corticosteroids at the time of death, no clear relation between the administration of these drugs and the onset of psychiatric symptoms could be established. Chronic liver disease. Five patients, 2 females and 3 males, died because of chronic liver disease that could not be related to any previous history of viral hepatitis, contact with hepatotoxic agents, or alcoholism. It was assumed that ulcerative colitis played a primary role in the liver disease in each of the 5 patients. All expired after 1953, having had ulcerative colitis for an average of 9.8 years. The mean age at death was 30 years. Three patients died from bleeding esophageal varices, 1 immediately following a splenectomy and a splenorenal shunt. Two died in hepatic failure. Autopsies were performed in all 5 patients. The final microscopic diagnoses included biliary cirrhosis in 3 cases, portal cirrhosis in 1, and active hepatitis with cirrhosis in 1. One patient was found at autopsy to have a localized cholangiocarcinoma. The colitis per se appeared less severe than in patients dying of cancer or of causes directly referable to ulcerative colitis. The patient records gave the impression that the liver disease largely dominated the clinical picture in each case. Review of X-rays and surgical pathology reports disclosed colon involvement to be severe in 2 cases, moderate in 2, and mild in 1. Phlebothrombosis. Several observations have been made regarding the association of venous thrombosis and ulcerative colitis. Three patients in the present series died because of complications of thrombophlebitis or its therapy. One patient developed an iliofemoral and vena caval thrombosis and died of a subarachnoid hemorrhage while being anticoagulated. There were 2 cases of fatal pul-
November 1969
MORTALITY IN ULCERATIVE COLITIS
monary embolism. As might be expected, patients dying with this complication were older than the majority of the group. The patient with the vena cava thrombosis was 37 years old at the time of death; the remaining 2 were 63 and 71 years of age, respectively. Additional complications of chronic ulcerative colitis were implicated as causes of death in 2 patients. One patient died of renal amyloidosis at the age of 16 after a 6-yeal' history of colitis. Pyoderma gangrenosum with confluent necrosis of large areas of the skin resulted in the death of a 59-year-old woman who had had ulcerative colitis for 12 years. Complications of therapy. A total of 14 patients died because of side effects of therapy rather than the disease itself. The use of blood and blood products indirectly accounted for 7 of these deaths. The final diagnoses included transfusion incompatibility reactions (3), fulminating serum hepatitis (2), and congestive heart failure due to overtransfusion (2). All of the fatalities occurred after 1949. Adverse reactions to drugs were implicated in three deaths. Steroids probably were instrumental in 1 instance of acute fatal upper gastrointestinal hemorrhage with ulceration and in 1 case of duodenal ulcer perforation. In both patients, there had been no history of acid-peptic disease prior to the use of steroids. The drugs were not employed as emergency measures, and the ulcerations did not occur as terminal events of a fulminating ulcerative colitis. One instance of renal failure was reported secondf}ry to renal tubular crystallization of sulfadiazine. Inadvertent trauma to the femoral artery in an attempted venipuncture resulted in a fatal iliofemoral arterial thrombosis in 1 case. Late complications of colon surgery resulted in 2 deaths (peritoneal adhesions and ileostomy stenosis).
Deaths Unrelated to Ulcerative Colitis Forty-five patients with ulcerative colitis, averaging 54 years of age, died for reasons apparently unrelated to the in-
485
testinal disease. Autopsies were performed on 35 (78%). Causes of death included myocardial infarction (14), cerebrovascular accidents (8), non-colonic malignancies (7), congestive heart failure (3), pneumonia (3), suppurative cholangitis (3), traumatic esophageal perforation (1), pulmonary fibrosis (1), chronic renal disease (1), and emphysema (1). There were three accidental deaths in this group. The average duration of ulcerative colitis in these patients was 12.0 years. Radiological Observations In an attempt to find a relationship between the extent of colon involvement and the ultimate cause of death, the latest barium examinations of the colon were reviewed in 105 of the 127 deceased patients. In another 17, only the radiologist's report was available, and 12 patients had no record of a barium enema. The radiological appearance of the colitis was graded as severe, moderate, or minimal, depending largely upon the extent of colon involvement. Inflammatory involvement of more than two-thirds of the length of the colon was arbitrarily graded severe, while minimal involvement implied that the barium examination was either normal or that inflammatory changes were limited to the rectum or rectosigmoid. Distribution of patients according to extent of disease is compared with the final diagnostic category in table 2. As in 2. Distribution of final diagnoses compared with degree of involvement of the colon on barium enema
T A BLE
486
MOROWITZ AND KIRSNER
prior reports, 11 ' 12 a striking relationship is seen between the occurrence of direct colitis and colitis-related deaths and the presence of severe involvement of the colon as seen upon X-ray. Of the 83 patients whose disease involved more than two-thirds of the colon, 70 died of causes either directly due to, or related to ulcerative colitis; only 13 deaths in patients with severe colitis were unrelated to their bowel disease. Conversely, 18 of 24 patients with minimal involvement died of causes unrelated to colitis. Thirty-six of the 42 direct colitis deaths (86%) occurred in patients with X-ray evidence of severe disease; a similar proportion was noted (79%) in patients whose deaths were colitis-related. On the other hand, in those with colitis-unrelated deaths, 18 of 40 colon X-rays (45%) showed minimal involvement, while only 13 (33%) were judged severe.
Chronological Observations Duration of disease. The average duration of disease prior to death appears to be increasing slightly for all patients (fig. 1) . Between 1930 and 1939, the over-all mean duration of illness wa!l 3.8 years, whereas between 1960 and 1966, it had increased to 14.4 years. However, a total
Vol . 57, No. b
of 25 patients died within 1 year of the onset of their illness, and only 7 patients were known to have had ulcerative colitis for more than 30 years. Age at death. The average age at time of death for all patients was only 43 years, but this also seems to be increasing with passage of time (fig. 2). Between 1930 and 1939, the mean age at death was 37 years, while between 1960 and 1966, it was 48 years. The distribution of all patients according to age at death is illustrated in figure 3. Ages at death ranged from 6 to 86 years. Interestingly, patients dying because of factors related to ulcerative colitis (group II) were younger (36 years) than those succumbing as a direct consequence of the bowel disease (group I). However, the group II patients usually had their disease for a longer period of time (11.7 years, compared with 7.4 years). The relatively low average age at death (54 years) of patients dying of factors apparently unrelated to ulcerative colitis raises several interesting speculations. The first, of course, is that the chronic bowel disease represents a damaging influence, in some unknown manner rendering the patient more susceptible to the development of degenerative disease or
- 15
15
Ul
a::
UJ
>-
z
10
UJ
-
10
Ul
UJ Ul
0
u. 0
z
0
5
5
~
a:: => 0
0
1930 · 34 1935-39
1940-44 1945-49 1950 -54 1955-59 1960-66
0
DATES OF DEATH
FIG. 1. Average duration of ulcerative colitis in deceased patients from 1930 to 1966.
November 1969
487
MORTALITY IN ULCERATIVE COLITIS 50
40 (/)
a: <[
w >-
30
~
w
20
~
<[
10
1930-39
1940-49
1950-59
1960-66
FIG. 2. Average age at time of death in all patients from 1930 to 1966. 30
25 (/)
,.._
z
w
20
;::
... 0 0:
15
w
(I)
::<
10
:::>
z
AGE- YEARS
FIG. 3. Distribution of all patients according to age at death.
noncolonic malignancy. Another possibility is that deaths from vascular occlusion may represent manifestations of enhanced intravascular clotting known to be associated with ulcerative colitis. While the average age at death of patients dying of myocardial infarctions was 67 years, the average age of those dying with cerebrovascular accidents was only 52 years. Number and distribution of deaths. This study includes only 34 deaths between 1930 and 1949; however, 103 deaths occurring between 1950 and 1966 are listed. Inasmuch as the survival time appears to be increasing, the increasing number of deaths over the years (fig. 4A) in part reflects the growth of the Gastro-
enterology Clinic at the University of Chicago (fig. 4B). Defining a true death rate from these figures is difficult, inasmuch as the total clinic population is uncontrolled and always fluctuating. As in prior reports, the majority of deaths occurring because of colitis took place in the first few years after the onset of clinical disease. This distribution is illustrated in figure 5. Of the 46 direct colitis deaths, 18 occurred within 1 year after diagnosis, and an additional 7 took place within 5 years. Although the colitis-related deaths were distributed more evenly over the study period, they also tended to cluster in the first years of disease. This probably reflected the early
488
MOROWITZ AND KIRSNER
incidence of suicide and complications of therapy. The carcinoma deaths accounted for a majority of the colitis-related deaths occurring between 10 and 20 years after diagnosis. The distribution of deaths during various therapeutic eras was compared to determine possible differences in mortality patterns (table 3). The period under study was separated, at 1950, into presteroid and steroid eras. The presteroid era was further divided into the period from 1930 to 1938, when antibacterials were not available, and from 1939 to 1949 when they were available. Between 1950 and 50
Vol. 57, No. 5
1966, 72 of 103 deceased patients received ACTH or steroids, and 31 did not. In the presteroid era, direct colitis deaths comprised 21 of a total of 34 deaths or 62%. Since 1950, the proportion has fallen to 24%, or 25 of 103 fatalities. A corresponding increase, however, is noted in the proportion of colitis-related deaths. For example, in the presteroid era, there were 7 colitis-related deaths among 34 patients or 21%. In the steroid era, this figure has risen to 38% or 39 of 103 patients. Extending these observations to the major final diagnoses themselves and again comparing the eras before and after
A
40 (/)
J: ~
<1:
w
30
0
~
z
w
20
~
<1:
Cl.
10
0
J 1930·34
193~ · 39
1940·44
194~·49
19~0-~4
19~~- ~9
1960·66
YEAR 1000
B
900 (/) ~
800
w
700
z
~
<1:
Cl.
~ ~
600 500
_J
0 u
400
~
300
z
200
w 100 0 1930·34 1935 · 39
1940·44 1945·49 1950· 54 1955-59 1960·66
YEAR FIG. 4. A, chronological distribution of ulcerative colitis patient deaths at the University of Chicago Clinic. B , growth of the ulcerative colitis population at the University of Chicago between 1930 and 1966.
November 1969
489
MORTALITY IN ULCERATIVE COLITIS
! :~ ll.. . .C OL~ .~S DE.:.H.S~- ~·- · L_~-~ - - - - - L-~- - L- ..
~
~z
::>
1:
~
.. - -
COLITIS RELATE D DEATHS
oJ •1- I
P
"
COLITIS U,.RELATEO DEATHS 7
I
5
' 20
10
.
25
- .... .30
35
YEAR OF ILLNESS
FIG. 5. Distribution of deaths in all ulcerative colitis patients according to year of illness.
1950 (table 4), we note that colon perforation accounted for 24% of the deaths before 1950 and 8% after; fulminating ulcerative colitis caused 15% of the deaths prior to 1950 and 7% after. The incidence of operative and postoperative deaths and mortality due to complications of medical treatment have remained essentially unchanged since 1950, but the incidence of carcinoma of the colon and rectum, chronic liver disease, suicide, and all colitis-related deaths has increased significantly. Likewise, the frequency of colitis-unrelated deaths has risen from 21 to 37%, reflecting in part the longer life of these patients. The increases in longevity and the changes in mortality patterns since 1950 appear to relate, at least in part, to the increasing use of ACTH and 3. Distribution of deaths in ulcerative colitis patients according to various therapeutic eras
T ABLE
No. of deaths Era Colitisdirect
Colitis- ~ related
Colitisunrelated
----- - - - - -- ·
Presteroid e ra (34 patients)
1930- 1938 1939- 1949 Steroid era tients)
I
4
1
17
6
4
2
4
9
21
30
18 21
(103 pa-
1950-1966 No steroids Steroids use d
4. Comparison of the incidence of the major final diagnoses in ulcerative colitis before and after 1950
TABLE
Cause of death
Incidence
I
1 193o-1949
- -- -- - -- - ·
Colon perforation Fulminating ulcerative colitis Operative -postoperat ive Carcinoma, colon and rectum Chronic liver disease Suicide Complications of medical t herapy Coli t is-un related deaths
195o-1966
· ---
%
%.
24
8 7 12 14 5 6
15 12 6 0 0 12 21
10
37
corticosteroids. 13 - 15 Nonetheless, experience in the choice and timing of surgery, increasing awareness of the major complications of colitis, and availability of antibiotics effective against gram-negative bacteria also have been important.
Discussion Although the patients described in this series provide useful information on the causes of death in ulcerative colitis and the trends from 1930 to 1966, the conclusions to be drawn with regard to the colitis population as a whole are limited for several reasons. First, the severity of the ulcerative colitis referred to the University of Chicago Clinic probably is greater than generally prevails. Second, the pa-
490
MOROWITZ AND KIRSNER
tients lost to follow-up probably can be assumed to have had milder forms of illness and, therefore, be less likely to die of ulcerative colitis or its complications. Similarly, we were more likely to learn of colitis or colitis-related deaths occurring elsewhere in our patients than of colitisunrelated deaths. Despite these factors, the statistics derived from this analysis are disturbing. The average age at death for all deceased patients was only 43 years, and the average duration of illness was 10.7 years. Even in those individuals in whom ulcerative colitis could not be implicated in the final cause of death, the average age at death was only 54 years. These data, and similar experiences in the literature, appear to indicate that the development of ulcerative colitis is a health-threatening and life-shortening event of significant proportions, particularly when inflammatory changes in the colon are extensive. The problems associated with ulcerative colitis, and probably with the other forms of inflammatory bowel disease, clearly are not limited to the bowel but involve every bodily system and structure. Comprehensive studies involving all clinical and investigative approaches, therefore, seem necessary in the further investigation of this complex disease. REFERENCES 1. Edwards, F . C. , and S . C. Truelove. 1963. The course and prognosis of ulcerative colitis. II. Long-term prognosis. Gut 4: 309-315. 2. Nefzger, M. D., and E . D. Acheson. 1963. Ulcerative colitis in the United States Army in 1944. Gut 4: 183-192. 3. Hawkins, H. D. 1909. Natural history of ulcerative colitis and its bearing on treatment. Brit. Med . J . 1: 765-770.
Vol . 57, No. 5
4. Hardy, T. L., and E. Bulmer. 1933. Ulcerative colitis: a survey of ninety-five cases. Brit. Med . J . 2: 812- 815. 5. Buzzard, E . M., J. S. Richardson, and R. W. D. Turner. 1938. Ulcerative colitis: the outlook for the patient. St. Thomas Hosp. Rep. 3: 55..:.67. 6. Willard, J. H., J . F. Pessel, J . W. Hundley, and H . L. Bockus. 1938. Prognosis of ulcerative colitis. J . A.M. A . 111: 2078-2084. 7. Wheelock, F. C., and R. Warren. 1955. Ulcerative colitis: follow-up ~tudies. New Eng. J. Med. 252: 421-25. 8. Banks, B. M ., B. I. Korelitz, and L. Zetzel. 1957. The course of non-specific ulcerative colitis: review of twenty years' experience and late results. Gastroenterology 32: 983-1012. 9. Cullinan, E. R., and I. P . MacDougall. 1957. The natural history of ulcerative colitis. Lancet 1: 487-489. 10. Lindner, A. E ., R. C. King, and R. J . Bolt. 1960. Chronic ulcerative colitis. A clinical appraisal and follow-up study. Gastroenterology 39: 153-160. 11. Bockus, H. L., J . L. A. Roth, E. Buchman, M. Kalger, W. R. Staub, A. Finkelstein, and A. Valdes-Dapena. 1956. Life history of nonspecific ulcerative colitis: relation of prognosis to anatomical and clinical varieties. Gastroenterologia (Base[) 86: 549-581. 12. Watts, J., F. T . de Dombal, G. Watkinson, and J. C. Goligher. 1966. Long term prognosis of ulcerative colitis. Brit. Med. J . 1: 1447- 1453. 13. Truelove, S. C., and L. J . Witts. 1955. Cortisone in ulcerative colitis. Final report on a therapeutic trial. Brit. Med . J. 2: 1041-1048. 14. Spencer, J. A., J. B. Kirsner, P. Mlynaryk, P. I. Reed, and W. L. Palmer. 1962. hnmediate and prolonged therapeutic effects of corticotrophin and adrenal steroids in ulcerative colitis. Observations in 340 cases for periods up to ten years. Gastroenterology 42: 113-129. 15. Korelitz, B. I. , and A. E. Lindner. 1964. The influence of corticotrophin and adrenal steroids on the course of ulcerative colitis: a .comparison with the presteroid era. Gastroenterology 46: 671-679.