Appendectomy protects against ulcerative colitis

Appendectomy Protects Against Ulcerative Colitis PAUL RUTGEERTS,* GEERT and GASTON VANTRAPPEN*

D’HAENS,*

MARTIN

*Department of Medicine, Division of Gastroenterology, Sint-Rafael, Capucijnenvoer, Leuven, Belgium

HIELE,*

KAREL GEBOES,?

University Hospital Gasthuisberg,

Back#ound/Aims: Defining risk factors for ulcerative colitis (UC) is important to better understand the pathogenesis of this idiopathic disease. One factor modulating the disease is smoking. A pilot study showed the absence of appendectomy in the medical history of patients with ulcerative colitis. The aim of the present case control study was to compare the relative risk of developing UC after appendectomy with the relative risk of developing UC with an intact appendix. Methods: One hundred seventy-four (84 females and 90 males, mean age 34.9 years) consecutive UC patients examined at our inflammatory bowel disease clinic or hospital ward, were included. Fifty-six had pancolitis (32%) and 118 (68%) suffered from left-sided colitis. The control group consisted of 161 consecutive patients examined at the orthopedic clinic (86 females and 75 males, mean age 40.9 years). Results: Two parameters, ab sence of appendectomy and smoking, were closely related to the development of UC. Before the onset of UC, only 1 of the 174 patients (0.6%) had undergone an appendectomy. Of the 161 controls, 41(25.4%) had undergone an appendectomy. The difference between the two groups was highly significant with an odds ratio of 59.1 (95% Cl, 18-189; P < 0.001). The relative risk of getting the disease associated with nonsmoking was 2.95 (95% Cl, 1.69-5.17). Conclusions: Appendectomy is a protective factor against UC.

suggesting

and tDepartment

that genetic

of Pathology, University Hospital

factors play a more significant

role in Crohn’s disease than in UC. It is clear that environmental

factors,

including

cigarette

late the course of IBD.’ The relative

smoking,

modu-

risk of UC devel-

oping in nonsmokers is definitely higher than the relative risk of UC developing in smokers. Ex-smokers usually develop the disease better understanding crucial

to identify

after they stop smoking. To gain of pathogenetic factors in UC, it is

more risk factors for this disease.

In a noncontrolled survey of life style issues, including dietary features and past medical history of UC patients, we noticed not only a high prevalence but also the absence of appendectomy.

of nonsmokers To define the

relative risk associated with absence of appendectomy, we carried out a case control study in a large cohort of patients

with UC. We compared

the data with the risk

associated with nonsmoking. The group of patients in whom the original observation was made was not included

in the present

case control

study.

Patients and Methods One hundred verified diagnosis terology

seventy-four

of UC examined

clinic or admitted

consecutive

patients

at the outpatient

to the hospital

with

gastroen-

ward were included.

There were 84 females and 90 males with a mean age of 34.9 9-91 years). Fifty-six patients (32%) suffered from pancolitis, and 118 (68%) had left-sided colitis. The control group consisted of 161 consecutive patients examined at the orthopedic-traumatology clinic of the same hospital. There were 86 females and 75 males with a mean age of 40.9

years (range,

he etiology of chronic idiopathic inflammatory bowel diseases (IBD), including Crohn’s disease and T ulcerative colitis (UC), remains unknown, perhaps partly because ders.

The

certain UC

IBD represents incidence

100,000 incidence Region

from

from

7 per

1965

to

in UC registered was found

the incidence

of heterogenous

of UC seems

areas. In Sweden,

increased

a group the

to be increasing

annual

100,000 1983.’

incidence

to more The

increase

in the Uppsala

to be entirely

of UC.’ Epidemiological

disor-

due

in

rates

than

in annual

to an increase

Care in

and life style stud-

exogenous factors are implicated in the pathogenesis, especially of UC.3 Twin studies show that concordance rates in identical twins are higher for Crohn’s disease (44%-84%) than for UC (6%-36%), ies have suggested

that

tained

years). Data were obtained

The presence of an appendectomy

by physical

using a standard scar was ascer-

examination.

of

12 per

Health

years (range, 4-86 questionnaire.

Statistical

Analysis

The relative risks (odds ratio) (and 95% confidence limits) of patients with no appendectomy versus patients with appendectomy and patients who were not smokers at the time of study versus patients who were current smokers were calculated by means of cross table analysis (Proc Freq; SAS Statistical

0 1994 by the American Gastroenterological Association 00185085/94/$3.00

1252

RUTGEERTS

GASTROENTEROLOGY

ET AL.

Software, Car-y, NC). Associated P values were calculated by means of X’ tests. Although there was no significantly different smoking behavior between men and women (x2, P = 0.35), the CochranMantel-Haenstel-based odds ratio for effect of smoking, controlling for gender, was also calculated. To correct for possible confounding and for age difference, the independent influence of appendectomy, smoking, sex, and age was analyzed by means of unconditional logistic regression analysis (proc probit, SAS).

manifestation

developing

have undergone appendix associated

than

Nonsmoking

with an increased

also found an independent This may be explained has its onset

in subjects

risk for developing negative

with UC underwent

dectomy

in the third

predisposed

as such is a protective

to UC are less or whether appen-

factor against the develop-

ment

of age because of chronic abdominal pain and not because of acute appendicitis. The pathological report for this

malities, protect against acute appendicitis who will develop UC. The latter hypothesis

could not be recovered.

During

the course of the

disease, one other patient underwent an appendectomy because of acute appendicitis at age 53. Of the 161 controls, 41 (25.4%) had undergone an appendectomy at the time of their visit. The estimated

relative

risk of UC

developing in subjects who have undergone an appendectomy is 59.1 times lower (95% CI, 18-189; P < 0.001) relative to the risk in UC developing in subjects with appendix

in place.

The estimated

relative

risk of UC

having developed in subjects who have undergone an appendectomy is 29.4 times lower (95% CI, 7-124; P < 0.001) relative to the risk in subjects with appendix in place. Ninety-two percent of the appendectomies in the control patients were performed before the patients were 35 years of age. As expected on basis of the literature, smoking habits before the onset of UC were different between patients and controls. The ratio between former smokers and nonsmokers on the one hand and current smokers on the other hand was higher in UC patients than in controls (15 3/2 1 versus 115/46; relative risk, 2.91; 95% CI, 1.64-5.15). The sex-adjusted odds ratio was 2.95 (95% CI, 1.69-5.17). Unconditional logistic regression analysis showed an independent positive association with the risk of developing ulcerative colitis among nonappendectomy patients, odds ratio 51 (95% CI, 7-375; P = O.OOOl), among nonsmoking patients, odds ratio 2.9 (95% CI, 1.5 - 5.5; P = O.OOl), and among former smoking patients, odds ratio 3.9 (95% CI, 1.9-8.2; P = 0.0002). There was an independent negative association with age with odds ratio for increase of age with 1 year 0.98 (95% CI, 0.965-0.995; P = 0.008). The influence of gender was not statistically significant.

Discussion The present study have very rarely undergone

shows that patients with UC appendectomy before the first

hypothesis

would

certain factors, such as altered motility

likely,

and the role of the appendix

system might

aggregated testine

imply

and mucin

that

abnor-

in patients seems most

in the gut immune

be crucial in this respect. The appendix

an important part of the gut-associated system, together with Peyer’s patches principal

with age.

fact that UC

of patients

an appendectomy before onset of the disease. The surgical procedure was carried out when the patient was 10 years

patient

are

peak in the fifth decade. It is

patients

of UC. The former

whose UC. We

association

by the well-known

in the majority

decade of life with smaller

who

and former smoking

prone to suffer from acute appendicitis

1 of the 174 patients

risk of

UC is much lower in subjects

appendectomy

is intact.

No. 5

of the disease. The relative

or having

not clear whether

Resutts Only

clinical

Vol. 106,

gut-associated immunological

lymphoid

tissues

form

affector compartment

and act as antigen

The mucosal lymphoid contain B cells composed

detectors

the

of the in-

and processors.

tissues of the appendix mainly of immunoglobulin M (30%),

immunoglobulin A (19%), and immunoglobulin (12%), and less than one third of the mononuclear are T cells composed

is

lymphoid tissue and tonsils. The

mainly

of OKT4+

G cells

helper-inducer

T cells, and only 9% are OKT8+ suppressor cytotoxic T cells6 Moreover, induction of concanavalin A-induced suppressor

T cells is less than

that

of helper

T cells.

Thus, normal adult appendiceal lymphocyte reactivity is predominated by helper T cells. The appendix is mainly a helper organ. It has been established that there is a lack of induction of suppressor T cells by epithelial cells from patients with IBD.’ We postulate that resection of the appendix, a predominant

helper organ, might

influence

between ileocolonic helper and suppressor in that manner protects against UC.

the balance function

and

When the disease becomes manifest, appendiceal inflammation, if present, is part of ulcerative pancolitis in continuity with adjacent involved cecum.8 Active mucosal inflammation of the appendix with sparing of the cecum has been described.’ Reports on acute appendicitis in patients with left-sided or ulcerative pancolitis have not been published, and in our series only one patient underwent an appendectomy during the course of the disease. We conclude that having an intact appendix is a risk factor for UC. The relative risk of developing UC with an intact appendix exceeds the risk factor associated with

UC AND APPENDECTOMY

May 1994

nonsmoking.

Removal

of the appendix,

a T cell helper

organ, might effect its protective action because it will change the balance in favor of suppressor T cell function.

References 1. Ekbom A, Helmick C, Zack M, Adami HO. The epidemiology

2.

3. 4. 5.

of inflammatory bowel disease: a large population-based study in Sweden. Gastroenterology 1991;100:350-358. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative proctitis in central Sweden 1965-1983: a population-based epidemiological study. Dig Dis Sci 1991;36:97-102. Calkins BM, Mendeloff Al. Epidemiology of inflammatory bowel disease. Epidemiol Rev 1986;8:60-91. Mac Dermott RP. lnflammatoly bowel disease. Current Opinion in Gastroenterology 1992;4:630-633. Tobin MV, Logan RFA, Langman MJS, McConnell RB, Gilmore IT.

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Cigarette smoking and inflammatory bowel disease. Gastroenterology 1987; 93:316-321. Kawanishi H. lmmunocompetence of normal human appendiceal lymphoid cells: in vitro studies. Immunology 1987;60:19-28. Mayer L, Eisenhardt D. Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease. J Clin Invest 1990;86:1255-1260. Jahadi MR, Shaw ML. The pathology of the appendix in ulcerative colitis. Dis Colon Rect 1976; 19:345-349. Davison AM, Dixon MF. The appendix as a “skip lesion” in ulcerative colitis. Histopathology 1990; 16:93-95.

Received July 12, 1993. Accepted December 14, 1993. Address requests for reprints to: P. Rutgeerts, M.D., Ph.D., Professor of Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Fax: 32-16 344419.