GASTROENTEROLOGY 2004;126:1504 1517
Clinical Epidemiology of Inammatory Bowel Disease:
Incidence, Prevalence, and Environmental Inuences
EDWARD V. LOFTUS, JR.
Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Although the incidence and prevalence of ulcerative
colitis and Crohns disease are beginning to stabilize in
high-incidence areas such as northern Europe and North
America, they continue to rise in low-incidence areas
such as southern Europe, Asia, and much of the devel-
oping world. As many as 1.4 million persons in the
United States and 2.2 million persons in Europe suffer
from these diseases. Previously noted racial and ethnic
differences seem to be narrowing. Differences in inci-
dence across age, time, and geographic region suggest
that environmental factors signicantly modify the ex-
pression of Crohns disease and ulcerative colitis. The
strongest environmental factors identied are cigarette
smoking and appendectomy. Whether other factors
such as diet, oral contraceptives, perinatal/childhood
infections, or atypical mycobacterial infections play a
role in expression of inammatory bowel disease re-
mains unclear. Additional epidemiologic studies to de-
ne better the burden of illness, explore the mechanism
of association with environmental factors, and identify
new risk factors are needed.
n the broadest sense of the term, epidemiology is the
I study of occurrence of illness. Although many of us
associate the discipline with the study of acute outbreaks
of illness (usually infectious), epidemiology still remains
vitally important in seeking clues to the etiology and/or
pathogenesis of chronic idiopathic diseases, including
Crohns disease and ulcerative colitis. The current lead-
ing hypotheses for the etiology of the inflammatory
bowel diseases (IBD) emphasize genetic predispositions
to dysregulation of the gastrointestinal immune system.1
Many authors have pointed to the 50% 60% concor-
dance of Crohns disease in identical twins2,3 to illustrate
the importance of genetic influences in IBD. However,
one must remember the flip side of the coinapprox-
imately 40%50% of individuals with identical genetic
makeup are discordant for Crohns disease, pointing to
the inescapable conclusion that environmental influences
play an equally important role in the development of
IBD. This article will review the descriptive epidemiol-
ogy of Crohns disease and ulcerative colitis and high-
light environmental factors thought to predispose to
these conditions.
Descriptive Epidemiology
Descriptive epidemiology is the study of disease
incidence, prevalence, and demographic factors such as
age, gender, and race or ethnic group. Variations of
incidence and prevalence of disease across age, gender,
race, geographic region, or time may yield clues to the
etiology of disease or at least identify areas that deserve
further scrutiny. Moreover, studies of incidence and prev-
alence provide valuable information about the burden of
illness to policy makers, funding agencies, resource plan-
ners, health care insurers, and pharmaceutic companies.
Such epidemiologic studies can be particularly difficult
to perform for IBD because the onset of illness may be
gradual, there is no single gold standard for diagnosis,
and the differential diagnosis is broad. Furthermore,
availability of diagnostic techniques, criteria for what
constitutes an IBD case, methods of case ascertainment,
and awareness of the diagnosis among physicians in a
particular region may vary considerably across studies,
making comparison of studies difficult.
Incidence and Prevalence
Incidence is the frequency of new cases over a
certain time interval and is expressed as an incidence rate
(the convention in the IBD literature is cases per
100,000 person-years). There are literally hundreds of
articles describing the incidence of Crohns disease and
ulcerative colitis in many regions of the world,4 and a full
enumeration of these articles is beyond the scope of this
review. Incidence rates of IBD from selected geographic
regions around the world are shown in Table 1, and
prevalence figures are shown in Table 2. In general, the
highest incidence rates and prevalence for both Crohns
disease and ulcerative colitis have been reported from
northern Europe,518 the United Kingdom,19 22 and
2004 by the American Gastroenterological Association
0016-5085/04/$30.00
doi:10.1053/j.gastro.2004.01.063
May 2004 CLINICAL EPIDEMIOLOGY OF IBD 1505

Table 1. Incidence Rates of Ulcerative Colitis and Crohns Disease From Selected Registries
Case Incidence Incidence Incidence
Author(s) (reference) Setting ascertainment dates of UCa of CDa
North America
Pinchbeck et al.23 Northern Alberta Population 1981 6 10
Hiatt et al.24 Northern California HMO 19801981 10.9 7.0
Stowe et al.25 Monroe County, NY Hospital 19801989 2.3 3.9
Kurata et al.26 Southern California HMO, outpatient 19871988 NA 3.6
HMO, hospital 1988 NA 5.4
Loftus et al.27,29 Olmsted County, MN Population 19841993 8.3 6.9
Bernstein et al.28 Manitoba Population 19891994 14.3 14.6
Blanchard et al.30 Manitoba Population 19871996 15.6 15.6
Europe
Shivananda et al.14 8 N. European cities Population 19911993 11.8 7.0
Shivananda et al.14 12 S. European cities Population 19911993 8.7 3.9
Scandinavia
Bjornsson et al.18 Iceland Population 19901994 16.5 5.5
Munkholm et al.9 Copenhagen County Population 19801987 9.2 4.1
Langholz et al.8
Moum et al.12,13 S.E. Norway Population 19901993 13.6 5.8
Roin et al.6 Faroe Isles, Denmark Population 19811999 20.3 3.6
Lapidus et al.15 Stockholm County Population 19851989 NA 4.9
United Kingdom
Rubin et al.22 North Tees Population 19851994 13.9 8.3
Yapp et al.21 Cardiff, Wales Population 19911995 NA 5.6
Kyle19 N.E. Scotland Population 19851987 NA 9.8
Northern Europe
Russel et al.16 S. Limburg, The Netherlands Population 19911994 10.0 6.9
Gower-Rousseau et al.10 N.W. France Population 19881990 3.2 4.9
Southern/Central Europe
Mate -Jiminez et al.34 2 Spanish regions Hospital 19811988 3.2 1.6
Manousos et al.35,36 Heraklion, Crete Population 19901994 9.4 3.3
Vucelic et al.32,33 Zagreb, Croatia Population 19801989 1.5 0.7
Trallori et al.37 Florence, Italy Population 19901992 9.6 3.4
Tragnone et al.38 8 Italian cities Population 19891992 5.2 2.3
Asia
Odes et al.42 Southern Israel Population 19871992 NA 4.2
Sood et al.46 Punjab, India Survey 19992000 6.0 NA
Yang et al.44 Seoul, Korea Population 19921994 1.2 NA
Morita et al.43 Japan Survey 1991 1.9 0.5
Africa
Wright et al.47 Cape Town, South Africa Population, white 19801984 5.0 2.6
Population, colored 19801984 1.9 1.8
Population, black 19801984 0.6 0.3
Latin America
Linares de la Cal et al.48 Colon, Panama Hospital 19871993 1.2 0
Linares de la Cal et al.48 Partido General de Hospital 19871993 2.2 0.03
Pueyrredon, Argentina

Adapted and reprinted with permission from Sandler RS, Loftus EV. Epidemiology of inflammatory bowel diseases. In: Sartor RB, Sandborn WJ,
eds. Kirsners inflammatory bowel diseases. 6th ed. Philadelphia: Saunders, 2004;245262.
NA, not available.
aCases per 100,000 person-years.

North America,2331 which are the geographic regions
that have been historically associated with IBD. How-
ever, reports of increasing incidence and prevalence from
other areas of the world such as southern or central
Europe,3238 Asia,39 46 Africa,47 and Latin America48
underscore that the fact that the occurrence of IBD is a
dynamic process.
In North America, incidence rates for IBD range from
2.2 to 14.3 cases per 100,000 person-years for ulcerative
colitis and from 3.1 to 14.6 cases per 100,000 person-
years for Crohns disease (Table 1). Prevalence ranges
from 37 to 246 cases per 100,000 persons for ulcerative
colitis and from 26 to 199 cases per 100,000 persons for
Crohns disease (Table 2). When extrapolated to an es-
timated combined population of 320 million persons in
the United States and Canada in 2003, this implies that
between 7000 and 46,000 persons are newly diagnosed
with ulcerative colitis each year and that as many as
1506 EDWARD V. LOFTUS, JR. GASTROENTEROLOGY Vol. 126, No. 6

Table 2. Prevalence of Ulcerative Colitis and Crohns Disease From Selected Registries
Case Prevalence Prevalence Prevalence
Author(s) (reference) Setting ascertainment date of UCa of CDa
North America
Pinchbeck et al.23 Northern Alberta Population 12/31/1981 37.5 44.4
Kurata et al.26 Southern California HMO 1988 NA 26.0
Loftus et al.27,29 Olmsted County, MN Population 1/1/1991 229 144.1
Loftus et al.31 Olmsted County, MN Population 1/1/2001 246 162
Bernstein et al.28 Manitoba Population 12/31/1994 169.7 198.5
Europe
Langholz et al.8 Copenhagen Population 12/31/1987 161.2 54
Munkholm et al.9
Kyle et al.19 N.E. Scotland, United Kingdom Population 12/31/1988 NA 147
Mate -Jiminez et al.34 2 Spanish regions Hospital 12/31/1988 43.4 19.8
Vucelic et al.32,33 Zagreb, Croatia Population 12/31/1989 21.4 8.3
Trallori et al.37 Florence, Italy Population 12/31/1992 121 40
Rubin et al.22 North Tees, United Kingdom Population 1/1/1995 243 144
Daiss et al.5 Tubingen, Germany Population 12/31/1984 24.8 54.6
Montgomery et al.20 United Kingdom Survey 1996 122 214
Asia
Fireman et al.40 Central Israel Population 1980 55.2 19.5
Grossman et al.41
Odes et al.39 Southern Israel Population 12/31/1985 70.6 NA
Odes et al.42 Southern Israel Population 12/31/1992 NA 50.6
Sood et al.46 Punjab, India Survey 1999 44.3 NA
Morita et al.43 Japan Survey 1991 18.1 5.8
Lee et al.45 Singapore Hospital 19851996 6.0 3.6
Yang et al.44 Seoul, Korea Population 12/31/1997 7.6 NA

Adapted and reprinted with permission from Sandler RS, Loftus EV. Epidemiology of inflammatory bowel diseases. In: Sartor RB, Sandborn WJ,
eds. Kirsners inflammatory bowel diseases. 6th ed. Philadelphia: Saunders, 2004;245262.
NA, not available.
aCases per 100,000 persons.

780,000 persons may have ulcerative colitis. Likewise,
between 10,000 and 47,000 residents of the United
States and Canada are diagnosed with Crohns disease
annually, and as many as 630,000 persons suffer from
Crohns disease. Rates seem to be highest in northern
locales (the so-called north-south gradient).23,2730
Studies of hospitalization rates for IBD among Medicare
recipients and U. S. military veterans also suggest a
north-south gradient,49,50 although exceptions to this
concept exist.51
In Europe, incidence rates range from 1.5 to 20.3 cases
per 100,000 person-years for ulcerative colitis and from
0.7 to 9.8 cases per 100,000 person-years for Crohns
disease (Table 1). The entire European population (in-
cluding non-European Union countries) has been esti-
mated to be approximately 580 million as of 2002. The
multicenter European Collaborative Study on Inflamma-
tory Bowel Disease (EC-IBD) reported blended incidence
rates between 8.7 and 11.8 cases per 100,000 person-
years for ulcerative colitis and between 3.9 and 7.0 cases
per 100,000 person-years for Crohns disease.14 Using
these figures produces estimates of between 50,000 and
68,000 new cases of ulcerative colitis diagnosed annually
throughout Europe and between 23,000 and 41,000 new
cases of Crohns disease. The EC-IBD quantified the
degree of north-south gradient of incidence in Europe (in
general, incidence rates of IBD were 40% to 80% higher
in northern locales), but this gradient was narrower than
previously believed.14 A study from northern England
suggested that the prevalence of IBD in 1995 was as high
as 387 cases per 100,000 persons (243 per 100,000 for
ulcerative colitis and 144 per 100,000 for Crohns dis-
ease).22 Extrapolating these figures across the European
population yields a maximal estimate of 2.2 million
persons afflicted with IBD.
Historically, IBD was rare on other continents, with
the exceptions of Israel, Australia, and South Africa.
However, the incidence of IBD, especially ulcerative
colitis, is rising in several areas previously thought to
have low incidence, including Japan,43 South Korea,44
Singapore,45 northern India,46 and Latin America.48 In
most of these areas, however, Crohns disease remains
rare.
The incidence of Crohns disease is rising in many
areas (Figure 1), but the incidence has stabilized in many
high-incidence areas, such as Scandinavia and Minnesota.
In Olmsted County, the prevalence of Crohns disease has
continued to rise despite a stable incidence rate, presum-
May 2004
Figure 1. Temporal trends in incidence rates (cases per 100,000
person-years) of Crohns disease in selected areas (Olmsted County,
Minnesota27; Cardiff, Wales, United Kingdom21; Rochester, New
York25; Iceland17,18; Aberdeen, Scotland, United Kingdom19; Helsinki,
Finland7; and Florence, Italy37).
ably because of longer life expectancies of Crohns disease
patients and possibly in-migration of patients. Similarly,
the incidence of ulcerative colitis for the most part has
stabilized in high-incidence areas but has continued to
rise in areas with formerly low incidence rates (Figure 2).
Several themes emerge after examining temporal and
geographic trends in IBD incidence. First of all, IBD
incidence seems low in developing countries (whether
this is due to low diagnostic awareness, confusion with
infectious causes of diarrhea, or a truly low incidence rate
remains unclear). As societies become more Western-
ized or industrialized, with attendant changes in life-
style and diet and perhaps other environmental expo-
sures, ulcerative colitis emerges, but the incidence of
Crohns disease remains low. Over time, Crohns disease
emerges, and its incidence ultimately matches that of
ulcerative colitis.
Demographic Features
There appear to be slight gender-related differ-
ences in IBD incidence. In general, there is a slight
female predominance in Crohns disease, although in
certain low-incidence areas a male predominance exists.
The female predominance, especially among women in
late adolescence and early adulthood, suggests that hor-
monal factors may play a role in disease expression. On
the other hand, if there is a slight gender predominance
in ulcerative colitis, it rests with males. Indeed, some
studies of ulcerative colitis incidence suggest that, al-
though overall incidence has stabilized, it continues to
rise in males (with a corresponding decrease in fe-
males).29
Crohns disease and ulcerative colitis are most com-
monly diagnosed in late adolescence and early adulthood,
but the diagnosis may occur at all ages. In a systematic
review of population-based cohorts of Crohns disease
CLINICAL EPIDEMIOLOGY OF IBD 1507
from North America, the mean age at diagnosis ranged
from 33.4 years to 45 years,52 whereas the median age at
diagnosis, available in only 1 paper,27 was 29.5 years.
Mean and median ages at diagnosis of ulcerative colitis
are, in general, 5 to 10 years later than those associated
with Crohns disease.18,29 Although some studies focus-
ing on IBD incidence among children have noted in-
creasing incidence rates, these increases have generally
mirrored increases in the overall population, and the
percentage of patients who are diagnosed in the pediatric
age range does not appear to have risen in recent years.
IBD has classically been thought to demonstrate a
bimodal age distribution (i.e., incidence peak in the
second or third decades in life followed by a second,
smaller peak in later decades), but, in several recent
epidemiologic studies, this has not been uniformly
found. It is not known whether these differences in age
distribution are real or represent variations in diagnostic
criteria and/or classification. In some studies of ulcerative
colitis, there are gender-related differences in late onset
disease. Men are significantly more likely than women to
be diagnosed in the fifth and sixth decades of life.
Racial/Ethnic Differences in Incidence and
Prevalence
Several studies suggest that the incidence of IBD
among African Americans is approaching that of whites.
Hospitalization rates for Crohns disease were similar
among whites and blacks in a southern California HMO,
and the prevalence of Crohns disease among blacks was
approximately two thirds that of whites.26 The incidence
of IBD among African-American children from Georgia
was estimated to be, at a minimum, 7 to 12 cases per
100,000 person-years for Crohns disease and 5 to 7 cases
per 100,000 person-years for ulcerative colitis.51 African
Americans composed 28% of the pediatric IBD cohort,
Figure 2. Temporal trends in incidence rates (cases per 100,000
person-years) of ulcerative colitis in selected geographic regions (Olm-
sted County, Minnesota29; Rochester, New York25; Iceland17,18; Flo-
rence, Italy37; Malmo, Sweden11; Heraklion, Crete, Greece36; and
Seoul, South Korea44).
1508 EDWARD V. LOFTUS, JR.
approaching the overall percentage of African Americans
in the Atlanta metropolitan area (41%) or the state of
Georgia (36%).51 In a prospective survey from the
United Kingdom, the risk of IBD among African-Car-
ibbean children was similar to that of white children,53
whereas a retrospective study of IBD incidence in Derby,
United Kingdom, showed that the risk of Crohns disease
among whites and African-Caribbean adults was simi-
lar.54
Although data are limited, it appears that Asian
Americans, Americans of Hispanic background, and ab-
original North Americans are less likely to develop IBD,
especially Crohns disease. A study of Medicare recipients
from the 1980s showed that hospitalizations for IBD
among Hispanics and Asian Americans were uncom-
mon,49 and similar findings were seen for Crohns disease
hospitalizations among members of a southern California
HMO.26 Aboriginal Canadians residing in Manitoba,
Canada, were less likely to develop IBD.30
Studies of migrant populations suggest that ethnic
and racial differences may be more related to lifestyle and
environmental influences than true genetic differences.
For example, until recently, IBD was thought to be rare
in the Indian subcontinent. However, South Asians who
have moved to the United Kingdom, and their offspring,
are at increased risk of ulcerative colitis relative to
whites,5557 and those who have moved to Singapore are
at increased risk relative to ethnic Chinese.45 Israeli
studies suggest a higher prevalence of IBD among Jews
from Europe and America compared with those from
Asia and Africa, but those differences may be narrowing
over time.40,42
Risk Factors for IBD
Cigarette Smoking
Since the first widely publicized report of an
inverse association between ulcerative colitis and ciga-
rette smoking,58 many studies have confirmed this un-
usual finding59 74 (Table 3). The odds ratio for develop-
ing ulcerative colitis among current smokers is
consistently less than 1; stated another way, current
smokers seem to have a significantly decreased risk of
ulcerative colitis. A 1989 meta-analysis noted that cur-
rent smokers are 40% as likely as those who have never
smoked to develop ulcerative colitis.75 The mechanism of
action for this unusual association remains unclear
potentially important effects of nicotine on rectal blood
flow, colonic mucus, cytokines, and eicosanoids have
been reviewed elsewhere.76,77 Interestingly, a similar in-
verse association with cigarette smoking and illness has
been noted for related conditions such as primary scle-
GASTROENTEROLOGY Vol. 126, No. 6
Table 3. Putative Risk Factors for Inflammatory Bowel
Disease
Family history of inflammatory bowel disease
Cigarette smoking (risk factor for Crohns, protective factor for
ulcerative colitis)
Appendectomy (protective factor for ulcerative colitis, risk factor
for Crohns?)
Oral contraceptives?
High sugar diet?
High fat diet?
Breastfeeding? (protective factor?)
Perinatal or early childhood infections?
Wild-type measles infection?
Attenuated live measles virus vaccine? (unlikely)
Mycobacterium paratuberculosis infection?
rosing cholangitis (PSC), with or without associated
IBD,78 80 and pouchitis.81 The protective effect against
PSC suggests a systemic protective effect rather than a
local effect in the colon.
In many of the above studies, former cigarette smokers
were noted to have an increased risk of ulcerative colitis
relative to those who never smoked.60,62,65 68,73,74 When
these results are pooled, it appears that exsmokers are
70% more likely than those who never smoked to de-
velop ulcerative colitis.75 Why this should be the case
remains unclear. Some have suggested that early gastro-
intestinal symptoms might lead to smoking cessation,
explaining the increased risk among exsmokers. How-
ever, even remote smoking cessation is associated with
increased risk of ulcerative colitis.66
Cigarette smoking may influence the course of ulcer-
ative colitis. In one study, active smokers were half as
likely to be hospitalized for ulcerative colitis as non-
smokers, whereas exsmokers were 50% more likely to be
hospitalized and twice as likely as current smokers or
those who never smoked to undergo colectomy.82 In
another study, approximately 45% of ulcerative colitis
patients who resumed smoking noted improvement in
symptoms, and those who improved smoked, on average,
twice as many cigarettes daily as those who did not.83
French smokers with ulcerative colitis who quit smoking
had more active disease, more hospitalizations, and
greater need for corticosteroids or azathioprine compared
with those continued to smoke.84
Two randomized, placebo-controlled trials of transder-
mal nicotine for active ulcerative colitis demonstrated
clinical improvement in 40%50% of patients receiving
nicotine (as compared with 9%24% in the placebo
groups); however, neither study demonstrated signifi-
cantly higher remission rates with nicotine.85,86 A ran-
domized trial of nicotine vs. placebo patches for main-
tenance of remission showed no benefit of nicotine over
placebo.87 Another randomized clinical trial compared
May 2004
transdermal nicotine with moderate-dose oral pred-
nisolone for active disease.88 The nicotine group had
fewer remissions and more side effects than the pred-
nisolone group. Only 1 in 5 patients in the nicotine
group reached full sigmoidoscopic remission in the
6-week trial.88 It is possible that the benefit of smoking
on ulcerative colitis depends on levels of nicotine higher
than can be provided with patches, or it may be that
other components of cigarette smoke contribute to the
protective effect of smoking.
In contrast to ulcerative colitis, several studies have
implicated cigarette smoking as a risk factor for Crohns
disease,64,67,68,89 91 and meta-analytic techniques suggest
that smokers are more than twice as likely to develop
Crohns disease.75 Former smokers are also at risk, but
the magnitude is less than that for current smokers. The
association between smoking and Crohns disease may
not apply to all ethnic groups or geographic regions
several Israeli studies have failed to demonstrate that
smoking is a risk factor for Crohns disease.74,92,93
Smoking can influence the clinical course of Crohns
disease. Patients with Crohns disease who smoke are
more likely to have ileal than colonic or ileocolonic
involvement,94,95 and smokers are much less likely to
have pure inflammatory Crohns disease (as opposed to
fistulizing or stenosing disease).96 Continued cigarette
smoking following surgical resection increases the risk of
recurrent disease.97100 In a Canadian study, women who
smoked were more than 4 times more likely to require
another surgery for recurrent Crohns disease than non-
smokers,97 and a dose-response effect was noted. Crohns
disease patients who smoke are more likely to require
immunosuppressive agents,100 and women who smoke
are more likely to have a poor health-related quality of
life.101 On a hopeful note, Crohns disease patients who
quit smoking note fewer exacerbations and require less
corticosteroids or immunosuppressive therapy to control
symptoms compared with patients who continue to
smoke.102
Passive cigarette smoking has also been linked to IBD
risk, but results have been conflicting. One study found
that adult subjects exposed as children to environmental
tobacco smoke in the home were half as likely to develop
ulcerative colitis.71 The effect of passive smoking in
childhood was comparable with that of active smoking in
adulthood. However, another study found that passive
smoking exposure at birth was significantly associated
with the development of either subtype of IBD.103 The
association for Crohns disease demonstrated a dose-re-
sponse relationship. Secondhand exposure to cigarette
smoke in childhood increased the risk of Crohns, but not
CLINICAL EPIDEMIOLOGY OF IBD 1509
ulcerative colitis, in a Swedish study.94 An Israeli study
of passive smoking among adults with IBD showed no
overall differences in exposure among IBD patients or
controls, although ulcerative colitis patients may have
had less exposure to secondhand smoke when a quanti-
tative index was employed.104
Appendectomy
Appendectomy appears to be protective for the
development of ulcerative colitis. The inverse association
was first noted in a multicenter study of pediatric
IBD,105 and it has been confirmed in over a score of
studies.106,107 A metaanalysis of 17 case-control studies
involving almost 3600 cases and over 4600 controls
showed that appendectomy was associated with a 69%
reduction in the subsequent risk of ulcerative colitis.108
Even in studies that employ multivariate analysis to
control for other important factors such as cigarette
smoking, the apparent protective effect of appendectomy
remains significant.
Cohort studies of the relationship between appendec-
tomy and subsequent risk of ulcerative colitis have
yielded conflicting results.109,110 A Swedish national in-
patient register was utilized to assemble a cohort of over
212,000 patients who had undergone appendectomy and
a cohort of age-, gender-, and location-matched con-
trols.109 These cohorts were followed for over 5 million
person-years for a subsequent hospital diagnosis of ulcer-
ative colitis. Those undergoing appendectomy had an
incidence of ulcerative colitis approximately three quar-
ters that of controls.109 Important factors associated with
a lower incidence of ulcerative colitis included appendec-
tomy before the age of 20 years and appendectomy for
appendicitis or mesenteric lymphadenitis (vs. abdominal
pain or other reasons).109 A Danish cohort of over
154,000 patients who had undergone appendectomy was
followed for over 1 million person-years for a subsequent
hospital diagnosis of IBD.110 Expected numbers of hos-
pitalizations for IBD were derived from previously pub-
lished national rates.111 The appendectomy cohort was
13% less likely than expected to be diagnosed with
ulcerative colitis, but this was not statistically signifi-
cant.110 Why these 2 large cohort studies yielded con-
flicting results remains unclear. The Swedish study ex-
cluded UC diagnosed within 1 year of appendectomy,
whereas the Danish study did not; however, even if these
UC diagnoses are included, the results are little
changed.109,110 Most of the evidence from the case-con-
trol and cohort studies suggests that appendectomy is a
protective factor for ulcerative colitis.
Similar to the effect of cigarette smoking, appendec-
tomy may influence not only the occurrence of ulcerative
1510 EDWARD V. LOFTUS, JR.
colitis but also its clinical course. In a Japanese multi-
center study, ulcerative colitis patients who developed
ulcerative colitis after appendectomy were diagnosed at
older age and were less likely to develop recurrent symp-
toms than colitis patients with an intact appendix.112 In
studies from France and Australia, ulcerative colitis patients
who had undergone appendectomy prior to diagnosis
were significantly less likely to require colectomy,113,114
and, in the case of the Australian study, significantly less
likely to require immunosuppressive therapy for control
of disease.113 Another Australian study confirmed the
older age at diagnosis among colitis patients who had
undergone previous appendectomy but could not dem-
onstrate greater need for immunosuppressive therapy or
colectomy.115 The effect of appendectomy on the clinical
course of patients with known ulcerative colitis is limited
to case reports and small case series, and results are
conflicting.
The effect of appendectomy on the future risk of
Crohns disease has also been examined in at least 16
studies.107 Most studies have suggested that appendec-
tomy is associated with future risk of Crohns disease,
but, in many of these studies, statistically significant
differences were not noted, whereas, in other studies,
appendectomies performed at the time of diagnosis of
Crohns disease were not excluded107 (some patients with
Crohns disease will initially present with a syndrome
mimicking appendicitis, and appendectomies performed
just prior to Crohns diagnosis may have been because of
undiagnosed Crohns disease). Andersson et al. followed
the large Swedish cohorts for the development of Crohns
disease and noted an increased risk of Crohns disease
following appendectomy even after excluding a diagnosis
within 1 year of the procedure.116 However, children
who underwent appendectomy before the age of 10 years
were less likely to develop Crohns disease.116 Those who
developed Crohns disease following a surgery for perfo-
rated appendicitis had a more aggressive form, requiring
intestinal resection at least twice as frequently as others,
whereas patients who underwent appendectomy for other
reasons had a less aggressive form of Crohns disease.116
The mechanisms whereby appendectomy protects
against ulcerative colitis but increases risk of Crohns
disease are unknown, but hypotheses abound.107 The
development of appendiceal inflammation or mesenteric
adenitis might protect against ulcerative colitis and/or
predispose to Crohns disease. Alternatively, removal of
the appendix might influence the mucosal immune sys-
tem of the gut in such a way as to reduce the risk of
ulcerative colitis but increase the risk of Crohns disease.
GASTROENTEROLOGY Vol. 126, No. 6
Oral Contraceptives
Several case-control and cohort studies have sug-
gested an increased risk of IBD in women who take oral
contraceptives. Cohort studies from the United States117
and the United Kingdom,63,118 involving over 80,000
women, pointed to a 40% to 3-fold increase in IBD risk,
but, in most instances, these results were not statistically
significant, especially after adjusting for cigarette smok-
ing. Case-control studies have also yielded somewhat
conflicting results.119 123 However, a 1995 metaanalysis
that pooled the results of 2 cohort studies and 7 case-
control studies derived an odds ratio for Crohns disease
among users of oral contraceptives, after adjusting for
smoking, of 1.4 (95% CI: 1.11.9).124 Women who used
oral contraceptives, after adjusting for smoking, were
29% more likely to develop ulcerative colitis, but this
did not reach statistical significance (95% CI:
0.9 1.8).124 Other case-control studies not included in
the metaanalysis, from western Washington state and
Italy, also suggest an association between oral contracep-
tive use and IBD, especially Crohns disease.125,126 Some
of the studies have suggested a dose response, with
higher risks for IBD seen among longtime users of oral
contraceptives119,123,125 or among users of high estrogen
dose preparations.125
Whether oral contraceptive use modifies the course of
existing IBD remains unclear. Although one study of
women enrolled in the placebo arm of a Crohns disease
trial pointed to oral contraceptive use as a predictor of
relapse,99 a prospective French study examining risk
factors for Crohns relapse did not find that oral contra-
ceptives were associated with recurrence.127
The bulk of evidence does suggest a weak association
between oral contraceptive use and IBD. The mechanism
for this association is not definitively known, but it is
thought that the thrombogenic properties of oral contra-
ceptives, in the setting of a process of multifocal, micro-
vascular gastrointestinal infarction, might play a role.128
Diet
Because dietary antigens are, next to bacterial
antigens, the most common type of luminal antigen, it is
logical to surmise that diet might play a role in the
expression of IBD. Furthermore, differences in diet
might explain the significant differences in IBD risk
across geographic regions and the increases in IBD inci-
dence in migrant populations. However, despite numer-
ous studies of dietary factors in IBD, no consensus has
emerged. Studies examining the association between diet
and disease are difficult to perform because of poor recall
of diet and the possibility that diet was subconsciously
May 2004
altered even before formal diagnosis because of gastroin-
testinal symptoms.
The most consistent association noted in dietary stud-
ies has been the link between increased sugar intake and
IBD, especially Crohns disease, first identified over 25
years ago.129 Numerous case-control studies have con-
firmed the association between sugar intake and Crohns
disease, and these have been reviewed elsewhere.130 Stud-
ies that have minimized difficulties with dietary recall by
studying patients diagnosed within 1 year have yielded
conflicting results, with some studies showing an asso-
ciation131133 but others not.134 A population-based,
case-control study from The Netherlands implicated
chocolate and cola drink consumption as possible risk
factors for IBD.135
The role of fat intake in the expression of IBD has not
been studied extensively, but some epidemiologic studies
have implicated monounsaturated and polyunsaturated
fats in both Crohns disease and ulcerative colitis.136,137
High intake of dietary fiber, fruit, or vegetables may be
protective against the development of IBD, but results
vary from study to study.133,135,138 This could very well
be a spurious finding in that patients with Crohns-
related bowel strictures may restrict intake of fiber-
containing foods to prevent symptoms.
The studies on dietary factors in IBD remain difficult
to interpret. Studies of dietary interventions (other than
elemental diets), such as low sugar diets, have been
disappointing,130 and certain restrictive diets advocated
on the Internet for treatment of IBD have not been
subjected to enough rigorous scientific analysis to rec-
ommend them.
Perinatal and Childhood Factors
It has been proposed that the expression of IBD
may be influenced by events in early childhood, such as
mode of feeding, domestic hygiene, or perinatal infec-
tions. Whether breastfeeding protects against the devel-
opment of IBD remains unclear. Although several stud-
ies have suggested an inverse association between breast-
feeding and IBD,139 143 in most cases, the odds ratios
were not statistically significant, and other studies have
not demonstrated such an association.105,144 146 In gen-
eral, the association has been stronger for Crohns disease
than for ulcerative colitis. Like studies of dietary factors
in IBD, these studies often suffer from long recall inter-
vals and potential for recall bias.
Perinatal infections, either in the infant or the mother,
might influence the expression of IBD. It was noted in a
study of IBD from central Sweden that incidence rates
were higher in the first half of the year.147 In the same
population, it was determined that IBD patients, espe-
CLINICAL EPIDEMIOLOGY OF IBD 1511
cially Crohns disease, were significantly more likely than
controls to have a birth date within 6 days of another
case.148 The medical records of over 250 IBD patients
born in 1 of these hospitals were compared with those of
over 500 controls, and those with a recorded perinatal
health event (i.e., infection or serious illness in mother
or child) had a 4-fold increased risk for IBD.144 In the
same study, infants from families of low socioeconomic
status were 3 times more likely later to develop IBD.144
Several studies have noted a higher frequency of gastro-
enteritis or diarrheal illness during infancy among future
IBD patients, but, in most of these studies, recall bias is
a concern.140,145,149 A history of frequent childhood in-
fections or exposure to antibiotics has also been proposed
as a risk factor for IBD.150
On the other hand, some have suggested that absence
of infections might be a risk factor for IBD (similar to the
sheltered child hypothesis in asthma). Crohns disease
(but not ulcerative colitis) is more common in those who
lived in houses with a hot water tap during child-
hood,151,152 and others have noted an inverse correlation
between infant mortality rates and IBD incidence rates in
various countries.153
Measles Infection or Vaccination
It has been proposed that perinatal or childhood
paromyxoviral infection might result in persistent infec-
tion of the vascular endothelium of the mesentery, re-
sulting in a chronic granulomatous vasculitis (Crohns
disease).154 In the decade following World War II, sev-
eral measles epidemics occurred in central Sweden, and it
was noted that the number of people born in the 3
months following the epidemic peaks, subsequently di-
agnosed with Crohns disease, was 46% higher than
expected.155 The same group identified 4 women who
had developed measles infection during pregnancy in the
1940s and found that 3 of the 4 children born had
developed Crohns disease; moreover, immunohisto-
chemistry identified measles virus antigen in the intes-
tinal tissue of the 3 patients.156 However, other studies of
the association between perinatal and/or in utero measles
infection have not been able to confirm these find-
ings,146,157,158 and the bulk of evidence does not support
the hypothesis that wild-type measles infection leads to
IBD.159
The same investigators who initially proposed persis-
tent measles infection as a cause for Crohns disease
suggested that attenuated live measles virus vaccine
might lead to IBD.160 The prevalence of IBD in a group
of 3500 people who had received live measles vaccine in
1964 was compared with that of a cohort of over 11,000
subjects who were born in the same week in 1958 who
1512 EDWARD V. LOFTUS, JR.
had not received vaccine. Those receiving vaccine were 2
to 3 times more likely to develop IBD160; however,
concerns have been raised about this studys methodol-
ogy because the means by which IBD cases were identi-
fied in these 2 cohorts differed considerably. Moreover,
several case-control studies in different locales have not
demonstrated significant differences in vaccination rates
(with either measles-mumps-rubella vaccine or other
forms of measles vaccine) among IBD cases and unaf-
fected controls.161163 Indeed, one of these studies, a
population-based report from 4 health maintenance or-
ganizations on the West Coast of the United States,
suggested that measles vaccination after the age of 18
months was associated with a decreased risk of IBD.163
Based on the available evidence, it would be difficult to
conclude that measles vaccination is a risk factor for IBD.
Mycobacterial Infection
Years ago, the similarities between tuberculosis
and Crohns disease were first noted.164 Johnes disease, a
chronic wasting diarrheal illness in ruminants and other
species characterized by granulomatous inflammation of
the intestine, is caused by Mycobacterium avium subspecies
paratuberculosis (MAP). This organism was first cultured
from the intestinal tissue of patients with Crohns disease
in the early 1980s,165 and this finding has generated 2
decades worth of controversy.166 169 Subsequent at-
tempts at recovery of atypical mycobacteria from cultures
have had variable success.166 The specificity of a positive
mycobacterial culture has been questioned because atyp-
ical mycobacteria can also be recovered from the intesti-
nal tissue of unaffected individuals.170 Initial studies of
MAP seroprevalence suggested higher rates of MAP an-
tibody formation in Crohns disease, but subsequent
studies have not been able to reproduce these findings.166
A similar theme has been seen in studies utilizing poly-
merase chain reaction technology to recover MAP DNA
from patients with Crohns diseasethe rate of detection
varies considerably, both among Crohns cases and unaf-
fected controls.166 However, several recent studies high-
light that a mycobacterial hypothesis for Crohns disease
cannot be completely discounted at the present time.
MAP DNA could be recovered in 40% of subepithelial
Crohns-related granulomas and 0% of granulomas from
other conditions such as foreign body granulomas and
sarcoidosis.171 In another study utilizing fresh ileocolonic
mucosal biopsy specimens, MAP DNA was recovered
from 92% of Crohns disease patients and 26% of con-
trols.172 After tissue was cultured in conditions favorable
to mycobacteria, MAP DNA was recovered in 42% of
cases and only 9% of controls.172
GASTROENTEROLOGY Vol. 126, No. 6
It stands to reason that, if MAP were a significant
pathogen in Crohns disease, antimycobacterial therapy
should be of benefit. On the other hand, some of these
antimycobacterial agents are broad-spectrum antibiotics
and would be active against many normal gut flora.
Although several open-label studies of antibiotic regi-
mens with antimycobacterial activity have suggested
clinical improvement,173175 the results from randomized
clinical trials are less compelling. A meta-analysis of 8
trials of antimycobacterial therapy for Crohns disease
yielded somewhat conflicting results.176,177 In the 2 trials
(total of 89 patients) in which both treatment arms
(antimycobacterial drugs vs. standard therapy) received a
tapering course of corticosteroids, the pooled odds ratio
favored antimycobacterial therapy.177 In the other 4 trials
(n 226), the pooled odds ratio favored standard ther-
apy.177 The authors concluded that antimycobacterial
therapy could not be recommended on the basis of this
evidence.176 Although the MAP hypothesis is an intrigu-
ing one, the burden of proof remains on the proponents
of the hypothesis to demonstrate unequivocally the link
between MAP and Crohns disease.
Conclusion
Despite years of investigation, the root causes of
IBD are yet to be identified. Descriptive epidemiologic
studies not only provide valuable information about the
burden of illness, they highlight differences in incidence
of IBD across age, time, and geographic region, suggest-
ing that environmental factors can significantly modify
the expression of these conditions. The strongest modi-
fying factors identified thus far include family history of
IBD, cigarette smoking, and appendectomy. Continued
efforts at understanding how these factors influence the
expression of IBD, and identifying new risk factors, are
needed.
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Received January 5, 2004. Accepted January 22, 2004.
Address requests for reprints to: Edward V. Loftus, Jr., M.D., Division
of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW,
Rochester, Minnesota 55905. e-mail: loftus.edward@mayo.edu; fax:
(507) 266 0335.
Dr. Loftus has served as a consultant for AstraZeneca and Novartis
and has received research support from AstraZeneca, Procter and
Gamble, and GlaxoSmithKline.