THE AMERICAN JOURNAL OF GASTROENTEROLOGY
1, 2000
© 2000 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Appendectomy and the
Development of Ulcerative Colitis: Results
of a Metaanalysis of Published Case-Control Studies
I. E. Koutroubakis, M.D., and I. G. Vlachonikolis, M.A., D.Phil.
Department of Gastroenterology, University Hospital of Heraklion, and Department of Social Medicine,
University of Crete, Heraklion, Crete, Greece
OBJECTIVE: Numerous epidemiological studies have been
performed to determine risk factors that might contribute to
the development of ulcerative colitis (UC). Recent studies
have focused on the role of appendectomy in the disease’s
pathogenesis. This report aims to review and analyze the
degree of evidence from recent published studies.
METHODS: Medline and Embase databases were scrutinized
for studies published between 1987 and January 1999. Ref-
erence lists from published articles, reviews, and abstracts
from major gastrointestinal (GI) meetings were also re-
viewed. All studies specifically designed to evaluate the
association between appendectomy and UC were selected.
Thirteen studies that satisfied our selection criteria were
evaluated by metaanalysis.
RESULTS: The 13 case-control studies collectively gathered
evidence from 2770 patients with UC and 3352 controls.
Combining the results of the individual studies gave an
overall odds ratio of 0.307 (95% confidence interval [CI] ⫽
0.249 – 0.377) in favor of appendectomy (p ⬍ 0.0001). This
suggests that appendectomy gives a 69% reduction in the
risk of developing UC (95% CI ⫽ 62%–75%). The test for
heterogeneity (of all 13 studies) was not significant (␹2 ⫽
16.213, d.f. ⫽ 12, p ⬎ 0.10). The influence of potential
confounding factors (mainly smoking) on these results
could be excluded.
CONCLUSIONS: The review of the literature and the meta-
analysis of the selected studies suggest that the inverse
association between appendectomy and UC is strong and
consistent. Further studies are needed to establish whether a
causal relationship exists. (Am J Gastroenterol 2000;95:
171–176. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION
When considering the etiology of ulcerative colitis (UC),
environmental and cultural factors or infections and medical
treatments may be important, as is a genetic predisposition
to the disease. The significant geographic variation in UC
incidence, the increased incidence of UC in urban areas in
comparison to rural areas, and the low rate of concordance
Vol. 95, No.
ISSN 0002-9270/00/$20.00
PII S0002-9270(99)00739-X
in monozygotic twins are epidemiological observations sug-
gesting an important role for factors such as diet, lifestyle,
or infections (1). However, only a consistent inverse asso-
ciation between UC and smoking habits has been docu-
mented (2, 3).
Recent epidemiological studies have assessed the role of
appendectomy in inflammatory bowel disease (IBD). Sev-
eral reports have shown a significant negative association
between appendectomy and UC (4 –14). This association
was less pronounced in other recent reports (9, 10, 15–17).
Moreover, two of these studies (16, 17) found no association
between appendectomy and UC when multivariate logistic
regression analysis was used.
On the other hand, in Crohn’s disease (CD), a positive
correlation with appendectomy has been observed in some
studies (4, 6, 15). However, it now seems evident that this
association may be due to unrecognized or subclinical CD at
the time of the removal of the appendix (10, 17).
The aim of this report was to review the literature con-
cerning the association between appendectomy and the de-
velopment of UC. The studies covered different countries,
using different methods, and various types of cases and
controls. To investigate the overall strength of the reported
association we performed a metaanalysis of the most com-
prehensive studies.
MATERIALS AND METHODS
All studies reported in the literature concerning the role of
appendectomy in UC, published between 1987–1999, were
identified. The identification of studies for evaluation in-
volved searches using the Medline and Embase databases
under the list terms “ulcerative colitis,” “Crohn’s disease,”
or “inflammatory bowel disease” and “appendectomy,” “ap-
pendicectomy,” or “appendicitis.” The reference lists from
published articles, reviews, and abstracts from major gas-
trointestinal (GI) meetings were also reviewed.
The identified studies were evaluated independently by
both authors, with respect to characteristics of the study
design. The following criteria were adopted: case-control
study, prevalent or incident cases attending IBD clinic,
172 Koutroubakis et al.
validation of date of appendectomy for both cases and
controls (i.e., appendectomy at a date before the onset of UC
for case patients), matched controls with no IBD or IBD-
related aspects, and method of data collection (personal
interview with structured questionnaire [SQ] or routine clin-
ical records).
The abstracted data from the various studies by the two
reviewers were compared. Only minor discrepancies were
found; these were resolved after discussion. Thirteen studies
provided sufficient information to enable them to be in-
cluded in the metaanalysis. Studies published only as ab-
stracts without sufficient information for validation of the
above criteria were not included. These thirteen studies were
also checked with respect to other criteria. A summary of
their strengths and weaknesses is presented in Table 1.
Statistical Methods
For each study, the odds ratio and its 95% confidence
interval (CI) were recalculated from the reported data using
standard methods (18). The recalculation was necessary to
ensure that in all studies an appendectomy in a case per-
formed after the diagnosis of UC was ignored. A further
check on the quality of the selected studies was the calcu-
lation of the power of the test for the odds ratio for each
study (18). This was based on a test at the 5% level of
significance with one-sided alternative hypothesis of a mod-
erate difference of appendectomy prevalences: 10% among
controls and 4% among UC patients. The overall (pooled)
odds ratio, combined across all 13 studies, and its 95% CI
was calculated according to DerSimonian and Laird (19).
Because the adopted criteria were not able to eliminate all
differences between the studies a further statistical test of
homogeneity was carried out. This is a ␹2 test of the null
hypothesis that the true risk in each of the 13 studies was the
same (homogeneity). If this hypothesis is rejected the esti-
mate of the overall odds ratio is adjusted by a simple
modification method (19).
RESULTS
The 13 case-control studies collectively gathered evidence
from 2770 patients with UC and 3352 controls. The results
displayed in Figure 1 indicate that all studies showed
marked inverse associations between prior appendectomy
and subsequent development of UC. Only in two studies
(15, 17) did the results not reach statistical significance at
the 5% level. It is interesting to note (Table 2) that all studies
except two (12, 13) had power ⬎60%, and the two studies
with no significant result had power 68% and 61%, respec-
tively.
Combining the results of the individual studies gave an
overall odds ratio of 0.307 (95% CI ⫽ 0.249 – 0.377) in
favor of appendectomy (p ⬍ 0.0001). This suggests that
appendectomy gives a 69% reduction in the risk of devel-
oping UC (95% CI ⫽ 62%–75%). The test for heterogeneity
AJG – Vol. 95, No. 1, 2000
(of all 13 studies) was not significant (␹2 ⫽ 16.213, d.f. ⫽
12, p ⬎ 0.10), indicating that the true risk in each of the 13
studied populations was the same and its estimate above is
valid, needing no further adjustment. (It can be seen, for
example, that the adjusted overall odds ratio of 0.292 [95%
CI ⫽ 0.224 – 0.379] is very close to the original estimate).
Excluding the two studies with the lowest power (12, 13) the
metaanalysis of the remaining 11 studies gave an overall
odds ratio of 0.297 (95% CI ⫽ 0.229 – 0.384).
DISCUSSION
The metaanalysis confirms that patients with UC are signif-
icantly less likely to have had appendectomy, compared
with controls. The metaanalysis provided a highly signifi-
cant negative association between appendectomy and UC
(odds ratio ⫽ 0.307; 95% CI ⫽ 0.249 – 0.377). This suggests
that removal of the appendix could have a protective effect
against the risk of developing UC.
The possibility that smoking, known to be negatively
associated with UC, could be a confounding factor has been
explicitly addressed in six of the 13 studies. In five of these
(7, 9 –12) it was confirmed that controlling for smoking
(using logistic regression) did not change the significant
odds ratios for appendectomy as a risk factor for UC. This
means that appendectomy and smoking have independent
associations with the risk of developing UC. The remaining
study (17) had a nonsignificant odds ratio and adjusting for
smoking did not change that.
Other potential confounding factors such as socioeco-
nomic status or diet cannot be excluded, but it is unlikely
that they would change the result of the metaanalysis for
three reasons:
1. Their associations with UC are much weaker and less
consistent than the independent associations of smoking
and appendectomy with UC.
2. In studies that controlled for such factors (mainly socio-
economic factors and domestic hygiene) the effect of the
latter did not change the significant odds ratios for ap-
pendectomy as a risk factor for UC. In one study (16)
when controlling for age, gender, and social class, the
effect of appendectomy in UC remained protective but
did not reach statistical significance (p ⫽ 0.094). How-
ever, when the appendectomies performed after the onset
of UC were excluded, statistical significance was re-
stored (p ⫽ 0.024).
3. Significant associations due to confounding effects are
neither consistent (proportion of studies showing signif-
icant associations in the same direction for an exposure)
nor so strong (magnitude of association) as those seen for
appendectomy and UC in the reviewed studies.
Three theories have been proposed to explain the associ-
ation between appendectomy and UC. The first is that pa-
AJG – January, 2000
Table 1. Summary of Characteristics of Studies Included in the Metaanalysis
Author
(Reference Number)
Gilat et al. (4)
Gent et al. (6)
Wurzelmann et al.
(15)
Rutgeerts et al. (7)
Smithson et al. (8)
Russel et al. (10)
Minocha et al. (9)
Breslin et al. (16)
Parrello et al. (11)
Kubba et al. (13)
Derby and Jick (12)
Duggan et al. (14)
Koutroubakis et al.
(17)
* Validation of date of appendectomy: for cases in relation to date of their UC diagnosis; and for controls in relation to date of UC diagnosis of matched case.
† IBD and eczema and morbidity in family, infections, treatments, fruit and vegetable consumption, socioeconomic factors; no adjusted odds ratio is reported.
SQ ⫽ standard questionnaire; GI ⫽ gastrointestinal; UC ⫽ ulcerative colitis; IBD ⫽ inflammatory bowel disease; CCFA ⫽ Crohn and Colitis Foundation of America;
SHO ⫽ senior house officer.
‡ Two studies are reported; only the second study is included as the first had underascertainment of appendectomies and was based only on computer records.
Appendectomy and Ulcerative Colitis 173
Appendectomy:
Prevalence/ Method of Data
Case/Control Source; Incidence Confounding Collection; Validation
Location Matching Status Factors of Date*
Multicenter, GI clinics/outpatients Prevalent cases; Multiple factors† SQ; case and control
international: GI and general ⬍25 yr old before onset of UC
N. America, population or
N. Europe, and orthopedic clinics;
Mediterranean well matched
Multicenter, UK GI clinics/general Prevalent cases Domestic hygiene and SQ; visit at home;
population; well social class at case and control
matched infancy before onset of UC
North Carolina US Members of CCFA/ Prevalent cases Infections and SQ; mailing and
closest neighbors; treatments; IBD in phone call; before
incomplete family; smoking onset of UC for
matching cases only
Leuven, Belgium GI clinic/orthopedic Prevalent cases Gender, age, and SQ; before (and after)
clinic; no matching smoking onset of UC for
cases only
Oxford, UK GI clinic/dermatology Prevalent cases No control of SQ; before (and after)
clinic; no matching with primary confounding factors onset of UC for
appendectomy cases only
South Limbourg, GI clinic-IBD Prevalent and Smoking Clinical records and
Netherlands registry/general incident cases by post; case and
population; well control before onset
matched of UC
Oklahoma US GI clinics and private Prevalent cases Gender, race, age, and SQ; before onset of
physicians/patients smoking UC for cases only
at Internal
Medicine; no
matching
Dublin, Ireland GI clinic/orthopedic- Prevalent cases Gender, age, social SQ by interview,
traumatology; no group, and smoking telephone, or mail;
systematic matching before onset of UC
for cases only
Multicenter, Italy GI clinics/orthopedic Incident cases Smoking, alcohol Clinical records and
and surgical units; consumption, area, by telephone;
well matched and occupation before onset of UC
for cases only
Newcastle, UK GI clinic/orthopedic Prevalent cases No control of Clinical records
clinic; no matching confounding factors reviewed by nurse
(cases) and SHO
(controls); before
onset of UC for
cases only
General Practice General Practice Prevalent cases Smoking Computer records, GP
Research (cases and and telephone;
Database controls); well before onset of UC
(GPRD), UK‡ matched for cases only
Nottingham, UK GI clinic/elective Prevalent cases Gender and age SQ; cases and control
surgery; well before onset of UC
matched
Crete, Greece GI clinic/General Prevalent and Gender, age, smoking, SQ by interview; case
population; well incident cases occupation and control before
matched onset of UC
174 Koutroubakis et al. AJG – Vol. 95, No. 1, 2000

experimental colitis model (TCR-␣⫺/⫺ mice), in which re-

Figure 1. Individual and pooled odds ratios (OR) (95% confidence
intervals) of ulcerative colitis for appendectomy. *Adjusted odds
ratio for heterogeneity.
tients predisposed to UC are less prone to suffer from acute
appendicitis due to coexistent factors such as altered intes-
tinal motility, reduced faecalith formation, and mucin ab-
normalities (20).
The second, and probably most likely explanation, is that
appendectomy is indeed a protective factor against UC.
Supporting this theory are the results of a study in an
moval of the appendix at a young age led to a marked
reduction in mesenteric lymph node cells at 6 months and
was associated with a suppression of the development of
IBD (21). Although the TCR mouse does not have the same
type of appendix as humans and the surgery in this study
was more extensive than a simple appendectomy, we think
that the results are still relevant. The appendix is an impor-
tant part of the gut-associated lymphoid system, together
with Peyer’s patches and tonsils. It may be that the resection
of the appendix influences the balance between ileocolonic
helper and suppressor function and in this manner protects
against UC (22). However, the failure of the incidence of
UC to rise during the long-term decline of appendicitis in
the West contradicts this suggestion (23).
The third possibility is that an infectious agent or a related
antigen is present in the appendix and may be involved in
the pathogenesis of UC in the predisposed individual. Two
recent studies (24, 25) reported that Prion protein (PrP) was
found in tonsillar tissue and appendix, respectively, in pa-
tients with a new variant of Creutzfeldt-Jakob disease
(nvCJD) (26).
The time of appendectomy in relation to the onset of UC
is important. The majority of the studies deal with the
history of appendectomy before the development of UC.
The prevalence of appendectomy after UC diagnosis was
evaluated in some of the studies (7, 8, 14), but the reported
number of cases is too small to draw conclusions. So far,
there are little published data about the course of UC when
appendectomy is performed after UC diagnosis. However,
there is reference in unpublished data that the disease seems
to be more mild after appendectomy (27). One study (8)
distinguished between primary appendectomy (surgery for

Table 2. Metaanalysis of 13 Published Case-Control Studies of Appendectomy and Risk of Ulcerative Colitis (UC)
Sample Size Appendectomy (%)
Author
(Reference Number) UC Control UC Control Odds Ratio 95% CI Power (%)
Gilat et al. (4) 133 266 3.01 9.77 0.286 0.098–0.838 69
Gent et al. (6) 229 229 3.93 13.97 0.252 0.117–0.541 80
Wurzelmann et al. (15) 181 141 1.66 5.67 0.280 0.073–1.076 68
Rutgeerts et al. (7) 174 161 0.57 23.60 0.019 0.003–0.138 69
Smithson et al. (8) 197 243 2.54 10.70 0.217 0.082–0.577 78
Russel et al. (10) 423 423 4.96 10.40 0.450 0.263–0.771 96
Minocha et al. (9) 193 394 5.18 17.77 0.253 0.127–0.503 84
Breslin et al. (16) 177 189 6.21 17.46 0.313 0.153–0.641 72
Parrello et al. (11) 536 755 7.65 19.87 0.334 0.232–0.481 99
Kubba et al. (13) 110 136 0.91 10.29 0.080 0.010–0.618 56
Derby and Jick (12) 82 80 6.10 20.00 0.260 0.090–0.748 44
Duggan et al. (14) 201 201 2.99 14.43 0.182 0.074–0.450 76
Koutroubakis et al. (17) 134 134 8.21 13.43 0.576 0.261–1.272 61

Pooled
Odds Ratio 95% CI

Total 2770 3352 0.307 0.249–0.377

0.292* 0.224–0.379
* Adjusted odds ratio for heterogeneity.
CI ⫽ confidence interval.
AJG – January, 2000
appendicitis) and incidental appendectomy (removal of the
appendix for other reasons). It found significant a negative
association between primary appendectomy and UC. How-
ever, studies with larger data sets, focusing on the difference
between these two groups, should reveal whether appendec-
tomy alone protects against UC or whether appendicitis
should be confirmed before appendectomy (28).
It has been suggested that hygiene during childhood could
influence the development of IBD and might play a role in
the association with appendectomy (4). However, two stud-
ies (6, 14) that used proxy measures for domestic hygiene
during childhood (mainly the availability of hot running
water) found an association with CD but not with UC.
Another important recent observation is the frequent oc-
currence of discontinuous appendiceal inflammation in pa-
tients with UC (29 –31). Histological examinations after
total colectomy (29, 30) and endoscopic observations (31)
showed that UC patients without involvement of the cecum
often have inflammatory lesions in the appendix. Combining
this finding with the low prevalence of appendectomy in
UC, it could be suggested that inflammation at one site in the
large intestine may trigger UC at a different site in predis-
posed individuals.
This systematic review has led to the suggestion that the
appendix seems to have an important role in the developing
mucosal immune system and should no longer be consid-
ered an evolutionary redundancy (32). The results of this
metaanalysis for our study on Crete (17) suggest that the
odds ratio did not reach statistical significance due to the
small sample size, or it could be that on Crete other factors
play a more important role. For a better understanding of the
cause and pathogenesis of UC, future epidemiological and
experimental studies will have to focus on the exact role of
the appendix.
ACKNOWLEDGMENT
We thank Professor A.S. Peña, Free University Amsterdam,
for his critical reading and helpful suggestions.
Reprint requests and correspondence: Ioannis G. Vlachonikolis,
M.A., D.Phil., Department of Social Medicine, University of Crete,
P.O. Box 1393, 71409 Heraklion, Crete, Greece.
Received Mar. 16, 1999; accepted Aug. 18, 1999.
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