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ORIGINAL CONTRIBUTIONS
Irritable Bowel Syndrome–Type Symptoms in Patients
With Inflammatory Bowel Disease: A Real Association
or Reflection of Occult Inflammation?
John Keohane, MB1, Caitlin O’Mahony, PhD1, Liam O’Mahony, PhD1, Siobhan O’Mahony, PhD1, Eamonn M. Quigley, MD, FACG1 and
Fergus Shanahan, MD, FACG1
OBJECTIVES:
Do gastrointestinal symptoms in patients with inflammatory bowel disease (IBD) in apparent
remission reflect the coexistence of irritable bowel syndrome (IBS) or subclinical inflammation?
The aims of this study were as follows: (i) to prospectively determine the prevalence of IBS symptoms
in IBD patients in remission; and (ii) to determine whether IBS symptoms correlate with levels of
fecal calprotectin.
METHODS:
Remission was defined by physician assessment: Crohn’s disease (CD) activity index ≤150 and
ulcerative colitis disease activity index ≤3, and serum C-reactive protein < 10, while off corticosteroids
or biologics. Quality of life (QOL) (by inflammatory bowel disease questionnaire), the hospital anxiety
and depression scale (HAD), and fecal calprotectin were measured.
RESULTS:
Rome II criteria for IBS were fulfilled in 37/62 (59.7%) of CD patients and by 17/44 (38.6%) of
those with ulcerative colitis (UC). However, fecal calprotectin was significantly elevated above the
upper limit of normal in both IBD patient groups, indicating the presence of occult inflammation.
Furthermore, calprotectin levels were significantly higher in CD and UC patients with criteria for IBS
than in those without IBS-type symptoms. QOL scores were lower and HAD scores higher among UC
patients with IBS symptoms in comparison to those who did not have IBS symptoms.
CONCLUSIONS: IBS-like symptoms are common in patients with IBD who are thought to be in clinical remission, but
abnormal calprotectin levels suggest that the mechanism in most cases is likely to be occult inflammation
rather than coexistent IBS.
Am J Gastroenterol advance online publication, 13 April 2010; doi:10.1038/ajg.2010.156
INTRODUCTION
Clinicians are frequently challenged to interpret gastrointestinal symptoms in patients with inflammatory bowel disease
(IBD) who, on the basis of conventional tests, appear to be in
remission. In two separate studies, irritable bowel syndrome
(IBS)-type symptoms were described in 33% of patients with
ulcerative colitis (UC) and in 42–57% with Crohn’s disease (CD),
who were in remission (1,2). How does the clinician interpret
such symptoms? Do they reflect the coincident occurrence of
IBS or the presence of persistent, but clinically undetected, lowgrade inflammation? This management dilemma is particularly
problematic in CD and, especially in those with disease confined to the small bowel, where frequent disease monitoring is
logistically difficult.
There is a statistically definable likelihood of coincidence of
IBD and IBS, as both syndromes are common with prevalence
rates in the developed world for IBD ranging between 0.1 and
0.2% (3) and for IBS from 9 to 12% (4,5) and both may significantly impact on quality of life (QOL) (6–10). However, in the
absence of an identifiable cause, or a specific biomarker for either
condition, both IBS and IBD are diagnosed clinically as being
mutually exclusive. In both cases, diagnosis requires not only
the presence of compatible clinical features with chronicity, but
also, the exclusion of differential diagnoses. For patients with an
established diagnosis of IBD, optimal management requires that
disease activity be monitored accurately and treated promptly
to minimize long-term complications. The risk of unnecessary
and undesirable use of corticosteroids or other durgs arises in
1
Department of Medicine, Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland. Correspondence: Fergus
Shanahan, MD, FACG, Department of Medicine, Alimentary Pharmabiotic Centre, and Cork University Hospital, University College Cork, National University of
Ireland, Cork, Ireland. E-mail: [email protected]
Received 30 July 2009; accepted 7 January 2010
© 2010 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
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nature publishing group
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Keohane et al.
patients in whom symptoms cannot be attributed to readily
identifiable inflammatory disease activity. Conventional clinical
activity indices and traditional laboratory markers of inflammation, such as C-reactive protein, frequently lack sufficient sensitivity to detect low-grade inflammation and to help clinicians
distinguish subclinical IBD from coexisting IBS.
To help address this, we selected patients with both CD and UC,
who were considered to be in clinical remission, on the basis of
predefined criteria and determined their prevalence of IBS-type
symptoms and the relationship of such symptoms to fecal calprotectin, which was used as a surrogate marker of subclinical inflammation. The results confirm the common occurrence of IBS-type
symptoms in patients with both forms of IBD, but suggest that subclinical inflammation is a more likely explanation than coexisting
true IBS.
METHODS
This study was approved by Cork University Hospitals ethics
commitee, and patient recruitment was between 1 July 2006 and
30 June 2007. Informed consent was obtained from all research
participants. A single gastroenterologist was responsible for
assessment of the IBD patients (FS) and a separate gastroenterologist for the IBS study patients (EQ).
Study subjects
All patients attending a specialized IBD clinic over an 18-month
period were prospectively reviewed. Consecutive patients in clinical remission were recruited for inclusion in the study. Remission
was defined as follows:
(i) Physicians global assessment (based on history and physical
examination),
(ii) C-reactive protein < 10 mg/l,
(iii) Absence of use of corticosteroids or biological agents over
the prior 6 months, and
(iv) CD activity index ≤150 (11) or an UC activity index ≤3 (12).
In no case did the physicians global assessment disagree with the
other three criteria of remission.
The Rome II criteria for IBS were used for the defintion of IBS
symptoms (13). Participants were, accordingly, divided into four
groups: CD with and without IBS symptoms and UC patients with/
without IBS symptoms. QOL was assessed using the inflammatory
bowel disease questionnaire (IBDQ) (14) and the hospital anxiety
and depression (HAD) scale (15).
To provide reference ranges for controls and IBS subjects, two
further groups were studied: 34 healthy female controls (average
age 24 years) without gastrointestinal symptoms and 41 female
Rome II IBS patients (average age 41 years) who were recruited
consecutively at a specialty clinic for this condition.
Fecal calprotectin
A stool sample was obtained from each patient and all samples
were frozen at − 80 °C for fecal calprotectin assay (16). Fecal calprotectin was measured by quantitative enzyme linked immunoThe American Journal of GASTROENTEROLOGY
sorbent assay using the Phical test (CALPRO AS, Oslo, Norway);
the procedure followed the manufacturer’s instructions. This is
a well validated and Food and Drug Administration-approved
assay for measuring fecal calprotectin and has been used in discriminating IBS from IBD (17), assessing disease activity in IBD
(18) and as a predictor of IBD relapse (19). This involves extracting the protein from as little as 100 mg of faeces and testing the
supernatant using an enzyme immuno assay specific for calprotectin. The mean optical densities of all samples tested in duplicate were matched to a standard curve with actual calprotectin
concentrations of standards (mean r2 = 0.984) and corresponding
mean optical density values on a xy linear system. All concentrations were obtained from absorbance readings within the linear range (min = 0.06, max = 1.2). No calprotectin measurements
were obtained from extrapolated data. To ensure accuracy, samples were assayed using at least two starting dilutions. Where samples fell outside the linear range of the standard curve, they were
diluted appropriately to achieve a measurement within the linear
range of the standard curve.
Statistical analysis
Descriptive statistics are expressed as percentages for categorical
data and compared using χ2-test. Parametric data were compared
using an unpaired t-test and nonparametric data with Mann–
whitney U-test. A P value < 0.05 was considered to be significant.
All calculations were performed by Graphpad Prism v4 and InStat
V3 (Graphpad, San Diego, CA, USA).
RESULTS
A total of 106 patients were recruited: 62 CD and 44 UC patients.
Despite being considered to be in clinical remission by the predefined criteria, 59.7% (n = 37) of CD patients and 38.6% (n = 17)
of UC patients fulfilled Rome II criteria for IBS.
Clinical features of patients with and without IBS-like symptoms
Tables 1 and 2 compare the baseline demographics of IBD patients
with and without IBS symptoms in the CD and UC populations,
respectively.
Among the CD patients, two factors, smoking status and CD
activity index score, differentiated those with IBS symptoms;
these patients were more likely to be smokers (P < 0.0008) and
to have higher CD activity index scores (53.4±31.3 vs. 35.6±35.6,
P < 0.044), although within the range considered as being in remission. Among the UC patients, the UC activity index score was
numerically higher in those with IBS symptoms but did not reach
statistical significance. Importantly, all other demographic features
were similar for those with and without IBS symptoms in both CD
and UC patient groups.
When classified according to disease location and phenotype
using the Montreal system (20), no significant difference was evident for those with and without IBS-type symptoms, but subset
numbers became too small for robust comparative statistics. Thus,
of the patients with CD and IBS-type symptoms, 40.5% (15) had
ileocolonic disease, 21.6% (8) had colonic only, and 37.9% (14)
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Table 1. Summary of CD patient characteristics
CD + IBS (n = 37)
Age mean ± s.d., years
(range)
Females/males
CD − IBS (n = 25)
42 + 11.6 (21 – 65) 38.3 + 9.8 (20 – 67)
22/15
Duration of disease,
11.2 + 7.7 (2 – 30)
years, mean + s.d. (range)
P value
0.3
10/14
0.25
11 + 8.7 (1 – 30)
0.97
Surgery
(Crohn’s-related)
67% (n = 26)
56% (n = 14)
0.15
Smokers
27% (n = 9)
8% (n = 2)
0.0008
62.2% (n = 23)
52% (n = 13)
0.2
0%
4% (n = 1)
0.13
0
0
NS
AZA/6MP
32% (n = 14)
37.8% (n = 7)
0.55
No meds
13.5% (n = 6)
20% (n = 4)
0.35
53.4 + 31.3
35.6 + 35.6
0.04
Medications
5-ASA
Sulfasalazine
Steroids
CDAI (mean ± s.d.)
5-ASA, 5-aminosalicylate; AZA, azathioprine; CD, Crohn’s disease; CDAI, CD activity
index; IBS, irritable bowel syndrome; 6MP, 6-mercaptopurine; NS, not significant.
Table 2. Summary of UC patient characteristics
UC + IBS (n =17)
UC − IBS (n = 27)
P value
Mean age + s.d.,
years, (range)
42 + 11.5 (18 – 56)
44 + 13.6 (23 – 67)
0.84
Females/males
12/5
14/13
0.36
Mean duration of
disease + s.d. (range)
12.1 + 9.3 (1 – 29)
10.3 + 6.3 (1 – 29)
0.49
Surgery (IBD-related)
None
None
NS
11.7% (n = 2)
11.1% (n = 3)
0.95
With regard to the distribution of UC; of those with IBS-type
symptoms, 29.4% (5) had proctitis, 35.3% (6) had left-sided or distal colitis, and 35.3% (6) had pancolitis. Similarly, of those without
IBS-type symptoms, 29.6% (8) had proctitis, 33.3% (11) had distal
colitis, and 29.6% (8) had pancolitis.
Fecal calprotectin in IBD patients with and without IBS-type
symptoms
Fecal calprotectin levels were significantly higher in CD
patients with IBS compared with those without (414.7±80.3 vs.
174.9±49.1 mg/kg, P = 0.0087) (Figure 1). The difference remained
statistically significant when smokers were excluded (CD + IBS,
425.8 + 101.7 vs. CD-IBS, 185.6 + 55.1 mg/kg; P = 0.037). Likewise,
UC patients with IBS had higher calprotectin levels compared with
those without IBS symptoms (591.1±172.5; 229.8±83.4 mg/kg,
P = 0.0041) (Figure 2). As with CD, when smokers were excluded,
the difference in calprotectin remained significantly different
for those with IBS-type symptoms (655.8 + 189.7) vs. those UC
patients without IBS (253.6 + 92.8; P = 0.0076). For both CD and
UC, the numbers of smokers were too small to analyze the smoking subsets alone. It is noteworthy that calprotectin levels for all
CD and UC patients greatly exceeded those of control subjects.
P = 0.01
500
Calprotectin(mg per kg
stool, mean ±s.e.)
ileal only. Of those with CD without IBS-type symptoms, 33.3% (8)
had ileocolonic disease, 25% (6) colonic only, and 41.7% (10) ileal
only. With regard to phenotype; of those with CD with IBS-type
symptoms, 48.6% (18) had stricturing disease, 40.5% (15) nonstricturing, non-penetrating, and 10.8% (4) penetrating disease.
Similarly, of those with CD without IBS, 33.3% (8) had stricturing disease, 58.3% (14) had non-stricturing, non-penetrating, and
8.3% (2) penetrating disease.
400
300
200
100
0
Medications
5-ASA
76.5% (n = 13)
62.9% (n = 17)
0.55
Sulfasalazine
11.7% (n = 2)
14.8% (n = 4)
0.77
0
0
NS
AZA/6MP
11.8% (n = 2)
29.6% (n = 8)
0.31
No meds
11.8% (n = 2)
14.8% (n = 4)
0.77
1.2 + 1.2
0.44 + 0.64
0.06
Steroids
UCAI (mean ± s.d.)
5-ASA, 5-aminosalicylate; AZA, azathioprine; CD, Crohn’s disease; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; 6MP, 6-mercaptopurine;
NS, not significant; UC, ulcerative colitis; UCAI, UC activity index.
© 2010 by the American College of Gastroenterology
CD–IBS
Controls
Figure 1. Fecal calprotectin levels in patients with Crohn’s disease, with
and without inflammatory bowel disease (IBS)-like symptoms.
P < 0.01
800
Calprotectin (mg per kg
stool, mean ± s.e.)
Smoker
CD+IBS
700
600
500
400
300
200
100
0
UC + IBS
UC – IBS
Controls
Figure 2. Fecal calprotectin in patients with ulcerative colitis, with and
without inflammatory bowel disease (IBS)-like symptoms.
The American Journal of GASTROENTEROLOGY
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INFLAMMATORY BOWEL DISEASE
IBS-Type Symptoms in Patients With IBD
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Keohane et al.
200
P = NS
HAD score (mean + s.e.)
Calprotectin (mg per kg stool)
150
125
100
75
50
15
15
10
10
5
5
0
0
+IBS
–IBS
Crohn’s disease
25
Controls
IBS
Figure 3. Fecal calprotectin levels in patients with inflammatory bowel
disease (IBS) and healthy volunteer controls (P = 0.67).
P = NS
P < 0.0001
225
225
200
200
175
175
150
150
125
125
+IBS
–IBS
Ulcerative colitis
Figure 5. Hospital anxiety and depression scores in patients with Crohn’s
disease and ulcerative colitis, with and without inflammatory bowel disease
(IBS)-type symptoms.
0
IBDQ (mean + s.e.)
INFLAMMATORY BOWEL DISEASE
175
P < 0.01
elevated in both CD groups, there was no significant difference between those with or without IBS symptoms: 10.6±1.2
vs. 10.2±1.5, P = 0.835 (Figure 5). In contrast, among the UC
patients, the HAD score was significantly higher for those
with IBS symptoms compared with those without: 8.6±1.2 vs.
5.2±0.6, P = 0.016 (Figure 5).
DISCUSSION
100
100
+IBS
–IBS
Crohn’s disease
+IBS
–IBS
Ulcerative colitis
Figure 4. Quality-of-life assessments (inflammatory bowel disease questionnaire, IBDQ) in patients with Crohn’s disease and ulcerative colitis, with
and without inflammatory bowel disease (IBS)-type symptoms.
Figure 3 illustrates the range of calprotectin levels for our healthy
control and IBS subjects; calprotectin levels were similar in both
groups (calprotectin (mg/kg), mean±s.e., control vs. IBS = 23.7±3.9
vs. 24.7±4.7, not significant) with the mean level in both groups
well below 50 mg/kg.
Quality of life
The impact of the presence of IBS-type symptoms on QOL among
IBD patients was assessed using the inflammatory bowel questionnaire (IBDQ) and the HAD (Figure 4). The IBDQ has a range
of 32–224, a low score corresponding to a lower QOL. Among
CD patients, the IBDQ did not differ significantly between those
with or without IBS symptoms: 175.0±4.7 vs. 186.7±5.1, P = 0.09.
However, among UC patients, the IBDQ score was a significantly
lower for those with IBS symptoms compared with those without:
179.2±6.1 vs. 205.9±2.2, P < 0.0001.
The HAD score consists of 14 questions, 7 for anxiety and
7 for depression. It has a range of 0–42 and was designed for
hospital general medical outpatients. A score of 0–7 for either
subscale is considered normal. Although the HAD score was
The American Journal of GASTROENTEROLOGY
While confirming what others have previously shown, namely,
that IBS symptoms are common among IBD patients in apparent remission (1,2), this study provides convincing evidence that
such symptoms reflect ongoing IBD activity. This conclusion is
supported, first, by the presence of substantially elevated levels
of the fecal marker calprotectin among IBD patients with IBStype symptoms, levels higher than those without IBS symptoms
and substantially higher than those of IBS patients and control
subjects, second, by higher IBD activity indices in the IBD–IBS
groups and, finally, by the observation that CD patients with IBS
symptoms were more likely to smoke.
In approaching this complex issue, to minimize confounding variables, we selected patients with both CD and UC who were, by predefined conventional criteria, considered to be in clinical remission,
although acknowledging that clinical remission may differ from
endoscopic or biochemical evidence of remission. In practice, clinical remission does not necessarily mean the absence of symptoms;
it may include symptoms of insufficient severity to be regarded as
active disease or to require a change of treatment. A greater dilemma
is the presence of symptoms due to coexisting IBS. Although confirmation of disease activity is relatively easy in UC, the diagnostic
dilemma may be particularly problematic in CD, particularly if confined to the small bowel. The problem is compounded by insufficient
correlation between disease activity indices with endoscopic findings and thereby, as reviewed elsewhere (21–24), reflecting the need
for biochemical markers, such as calprotectin.
Until recently, the notion that at least some forms of IBS and
IBD could be related and, therefore, coexist would have been dismissed by many clinicians. There is, however, ample evidence for
the presence of low-grade inflammation or immune dysfunction
VOLUME 104 | XXX 2010 www.amjgastro.com
in IBS (25–27) and it appears that, at least in some instances, IBS
may represent an aberrant mucosal response to disturbances in
the intestinal microbiota (28–30), thereby, echoing current theories of IBD pathogenesis. Finally, an extensive literature attests
to the potential for low-grade inflammation, in IBD, to produce
symptoms reminiscent of IBS (31,32). In the past, the clinician
attempting to distinguish active IBD from superimposed IBS
was hampered by the absence of a sufficiently sensitive marker of
inflammatory activity and had to rely on clinical activity indices
such as the CD activity index (11). The advent of a well validated
and sensitive fecal marker of intestinal inflammation, fecal calprotectin, offers the potential to resolve these issues. Calprotectin is
a calcium- and zinc- bound protein that accounts for 60% of the
soluble proteins in the cytosol of neutrophil granulocytes. It is a
marker of neutrophil turnover and is released into the intestine
during colonic inflammation. It is resistant to colonic degradation
and can be easily measured in the stool by means of an enzyme
linked immunosorbent assay (16).
This study confirms the validity of calprotectin in distinguishing
IBD from both IBS and control subjects (17–19,33–35) and again
illustrates that calprotectin levels are within the normal range in
IBS (17,33,34). As neutrophils are not a feature of the immunoinflammatory changes found in the mucosa of some patients with
IBS, an elevated fecal calprotectin would not be expected in such
patients. Most importantly, calprotectin levels were considerably
higher in the IBD patients with IBS symptoms than in IBS or control subjects, and were comparable with those reported in IBD
patients who were about to relapse (19), providing strong support
for our contention that IBS symptoms in our IBD patients were,
indeed, reflective of ongoing activity of their IBD. In short, lowgrade IBD can produce IBS-type symptoms but the development
of such symptoms reflects the nonspecificity of gut’s symptomatic
repertoire. Regardless of their compatibility with available diagnostic criteria for IBS, their presence, in the context of IBD, does not
equate to a diagnosis of IBS and emphasises the caution that needs
to be exerted in interpreting such symptoms in the IBD patient. In
these challenging situations, which are most likely to occur in the
patient with small intestinal CD, as ongoing disease activity can be
fairly readily detected in UC by means of colonoscopy or flexible
sigmoidoscopy, the clinician has to balance the risks of inappropriate imaging (36) and empiric therapy against the need to correctly
identify the source of the patient’s symptoms. We contend that
fecal calprotectin and, perhaps, other fecal markers of inflammatory activity, may help to resolve this clinical dilemma. An analogous situation may arise in celiac disease in which IBS symptoms
may not only feature prominently at the time of presentation but
may also persist following apparent institution of a gluten-free diet
and contribute to impaired QOL (37,38); here the availability of
highly sensitive and specific antibodies that can be detected in the
serum as well as a low threshold for the performance of duodenal
biopsy have contributed greatly to diagnostic accuracy.
What do these findings tell us about relationships between IBS
and IBD? While the observation that IBS-type symptoms in IBD,
though frequent, are reflective of low-grade IBD activity rather
than coincident or related IBS, tends to emphasize that these are
© 2010 by the American College of Gastroenterology
distinct entities, it also provides a further illustration of the ability of intestinal inflammation, whether occurring in the context
of IBD or celiac disease, to lead to “functional” symptoms and
underlines the need for caution, by the physician, in the interpretation of such symptoms in these contexts. Finally, these findings also highlight the distinctive nature of the immune-mediated
processes that are operative in IBD and IBS (39). Not only is IBS
unlikely to lead to IBD (40), but also several features of their
mucosal and systemic immunology are quite different. Most
obviously, frank, light microscopic inflammation, a hallmark of
IBD, is not a feature of IBS and, while a variety of abnormalities
in the mucosal immune response have been documented in IBS
at a molecular level, their nature appears quite different to IBD.
One recent report, for example, documented reduced expression,
in IBS, of a number of chemokines and cytokines, which were all
quite clearly elevated in IBD (28). Furthermore, the scale of any
of the immunological changes seen in IBS is orders of magnitude
lower than that reported in IBD.
In acknowledging fundamental differences between IBD and
IBS, this study should not be interpreted as support for a conceptual biomedical dichotomy of organic vs. functional disease. The
limitation of these and other descriptors has been addressed by us
elsewhere (41), and a more unifying or integrated model of IBS
and IBD has been presented by others (42).
In summary, although IBS-like symptoms are common among
IBD patients in apparent remission and may lead them to qualify
for a diagnosis of IBS according to current criteria, it is evident
that such symptoms reflect ongoing, although subclinical, activity
of IBD and their presence should always be interpreted as such.
Bottom line, IBD is IBD unless proven otherwise!
CONFLICT OF INTEREST
Guarantor of the article: Fergus Shanahan, MD, FACG.
Specific author contributions: F.S. and E.M.Q. designed the study
and helped to assess the patients. J.K. was the main effector of the
study and the other authors helped with assays and analysis.
Financial support: The authors are supported, in part, by Science
Foundation Ireland in the form of a Centre grant, and by the Higher
Education Authority of Ireland.
Potential competing interests: None.
Study Highlights
WHAT IS CURRENT KNOWLEDGE
3Distinguishing occult inflammation from concomitant
irritable bowel syndrome (IBS) is an important diagnostic
dilemma in patients with inflammatory bowel disease (IBD).
3We confirm that IBS-like symptoms are common in both
Crohn’s disease and ulcerative colitis.
WHAT IS NEW HERE
3For patients judged to be in clinical remission, fecal
calprotectin levels are higher in patients with IBS-like
symptoms than in those without such symptoms.
3Subclinical inflammation should be sought first before
assuming a diagnosis of coexisting IBS.
The American Journal of GASTROENTEROLOGY
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Keohane et al.
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