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A Meta-Analysis of the Utility of C-ReactiveProtein, Erythrocyte Sedimentation Rate, Fecal
Calprotectin, and Fecal Lactoferrin to Exclude
Inflammatory Bowel Disease in Adults With...
Article in The American Journal of Gastroenterology March 2015
Impact Factor: 10.76 DOI: 10.1038/ajg.2015.6 Source: PubMed
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5 authors, including:
Jacob E Kurlander
University of Michigan
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William Chey
University of Michigan
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FUN
CTIONALGIDISORD
ERS
44
TheAmerican Journal ofGASTROENTEROLOGY VOLUME 110 |MARCH 2015 www.amjgastro.com
ORIGINAL CONTRIBUTIONS
INTRODUCTION
Irritable bowel syndrome (IBS) is a prevalent symptom-based
disorder that is characterized by the presence o abdominal pain
and altered bowel habits (1). IBS affects 7 to 15% o adults in the
United States (1,2) and is associated with a lower quality o lie
and annual expenditures well in excess o 20 billion dollars (3,4).
It has been suggested that patients with typical symptoms and noalarm eatures such as overt gastrointestinal bleeding, unexplained
iron deciency anemia, unintentional weight loss, symptom onset
afer age 50 years, nocturnal diarrhea or a amily history o inam-
matory bowel disease (IBD), colorectal cancer, or celiac disease
do not require exhaustive testing beore establishing a condent
diagnosis o IBS. Te American College o Gastroenterology rec-
ommended only routine serologic screening or celiac disease in
patients with diarrhea-predominant IBS or mixed IBS and colonic
mucosal biopsies or microscopic colitis when perorming colo-
noscopy in patients with diarrhea-predominant IBS (5). Despite
these recommendations, a signicant proportion o primary care
physicians and gastroenterologists view IBS as a diagnosis oexclusion and, as such, order multiple diagnostic tests to rule out
various organic diseases beore condently diagnosing IBS (6).
One o the main concerns o primary care physicians and gas-
trointestinal specialists when evaluating a patient with abdominal
pain and altered bowel habits is IBD. Despite data to suggest that
A Meta-Analysis of the Utility of C-Reactive Protein,
Erythrocyte Sedimentation Rate, Fecal Calprotectin,and Fecal Lactoferrin to Exclude Inflammatory Bowel
Disease in Adults With IBS
Stacy B. Menees, MD, MS1, Corey Powell, PhD2, Jacob Kurlander, MD1, Akash Goel, MD3and William D Chey, MD, AGAF, FACG, FACP1
OBJECTIVES: Irritable bowel syndrome (IBS) is viewed as a diagnosis of exclusion by most providers. The aim of our
study was to perform a systematic review and meta-analysis to evaluate the utility of C-reactive protein
(CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin, and fecal lactoferrin to distinguish
between patients with IBS and inflammatory bowel disease (IBD) and healthy controls (HCs).
METHODS: A systematic online database search was performed. Included studies were prospective, adult,
diagnostic cohort studies with any of the four tests. The means and s.d. values of biomarker
logarithms were estimated based on studies that gave medians and either confidence intervals for the
median, interquartile ranges, or ranges. We used a Naive Bayes approach to estimate the probability
of being a HC, having IBS, or having IBD based on the biomarker values.
RESULTS: Systematic review identified 1,252 citations. After cross-referencing medical subject headings,
detailed evaluation identified 140 potentially relevant journal articles/abstracts for CRP, ESR,
calprotectin, and lactoferrin of which 4, 4, 8, and 2 fulfilled our inclusion criteria, respectively. None
of the biomarkers reliably distinguished between IBS and healthy controls. At a CRP level of 0.5 or
calprotectin level of 40g/g, there was a 1% probability of having IBD. Individual analysis of ESR
and lactoferrin had little clinical utility.
CONCLUSION: CRP and calprotectin of 0.5 or 40, respectively, essentially excludes IBD in patients with IBS
symptoms. The addition of CRP and calprotectin to symptom-based criteria may improve the
confident diagnosis of IBS.
Am J Gastroenterol2015; 110:444454; doi:10.1038/ajg.2015.6; published online 3 March 2015
1Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan, USA; 2Center for Statistical Consultation and Research (CSCAR),
University of Michigan, Ann Arbor, Michigan, USA; 3Division of Internal Medicine, Columbia University, New York Presbyterian, New York, New York, USA.
Correspondence: William D. Chey, MD, AGAF, FACG, FACP, Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, SPC
5362, Ann Arbor, Michigan 48109-5362, USA. E-mail: [email protected] 31 July 2014; accepted 5 January 2015
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2015 by the American College of Gastroenterology TheAmerican Journal ofGASTROENTEROLOGY
4
Meta-Analysis of Biomarkers for Identifying IBS
the prevalence o IBD is low in patients with IBS symptoms and no
alarm eatures (7,8), numerous studies have described signicant
symptom overlap between patients with IBD and IBS (911). In
addition, the potential clinical and medicolegal consequences o
misdiagnosing an IBD patient with IBS can be substantial. As such,
a simple, inexpensive means by which to rule out IBD in patients
with suspected IBS would be o considerable value.
Candidate biomarkers that may be helpul to screen or condi-
tions that lead to a systemic inammatory response include sero-
logic-, tissue-, and stool-based tests. Both S100A and B-2 deensin
are available or investigational use only. S100A has been ound
in two separate studies to be overexpressed in rectal mucosa in
IBS patients (12,13), whereas B-Deensin-2 has been shown to be
elevated within tissue and stool (14). Commercially available bio-
markers include serologic (C-reactive protein (CRP) and eryth-
rocyte sedimentation rate (ESR)) and stool-based (calprotectin,
lactoerrin) tests. CRP is produced by hepatocytes in response
to proinammatory cytokines such as interleukins 1 and 6. An
elevated ESR occurs when hepatocytes and the immune systemproduce proteins that cause red blood cells to aggregate and
collect at the bottom o a test tube. Both tests can be elevated in
IBD and provide a measure o disease activity. More recently, two
neutrophil granular proteins, calprotectin and lactoerrin, that
are released rom activated neutrophil cells into the eces have
been studied as an adjunct in IBD diagnosis. Calprotectin is a
calcium and zinc protein ound in neutrophils and monocytes
and comprises 60% o the cytosolic protein content o neutro-
phils. Its elevation in the eces is likely a result o cell disrup-
tion and death, although it can be actively secreted. Lactoerrin
is an iron-binding glycoprotein that is secreted by most mucosal
membranes and is a major component o polypmorphonuclearneutrophil secondary granules. Tese polypmorphonuclear
neutrophils are the primary components o the acute inamma-
tory response.
Recent studies have assessed the ability o CRP, ESR, ecal cal-
protectin, and ecal lactoerrin to discriminate between healthy
persons, patients with conrmed IBD, and patients with IBS. Te
aim o our study was to perorm a systematic review and meta-
analysis to evaluate the utility o CRP, ESR, ecal calprotectin, or
ecal lactoerrin to aid in distinguishing between IBS, IBD, and
healthy patients.
METHODSStudy protocol
Using the Cochrane handbook or systematic reviews o diagnos-
tic test accuracy as a guide, a standard protocol or study identi-
cation, inclusion, exclusion, and data abstraction was developed
and used to identiy potential studies or this systematic review
and meta-analysis (15). Data were recorded according to the pre-
erred reporting items or systematic reviews and meta-analyses
described by the PRISMA (Preerred Reporting Items or System-
atic Reviews and Meta-Analyses) guidelines (16). A systematic
search o relevant abstracts in any language was perormed or
CRP, ESR, ecal calprotectin, and ecal lactoerrin in the ollow-
ing electronic databases: Medline (1950 to March 2014), EMBASE
(1947 to March 2014), Cochrane library (1993 to March 2014),
Web o Science (1900 to March 2014), and PubMed (1950 to
March 2014). Bibliographies rom relevant gastrointestinal meet-
ings including Digestive Diseases Week, Te Annual Meeting o
the American College o Gastroenterology, and the United Euro-
pean Gastroenterology Week rom years 20002013 were manu-
ally searched or relevant studies. Medical subject headings or
our literature review included CRP, C-reactive protein, ESR,
blood sedimentation, westergren, Leukocyte L1 Antigen
Complex, calprotectin, ecal calprotectin, calgranulin, ecal
lactoerrin, or lactoerrin. Tese subject headings were cross-
reerenced with IBS, irritable bowel syndrome, IBD, inam-
matory bowel disease, crohn, and colitis, or completeness.
Study selection and data abstraction
Studies included in this meta-analysis were prospective diagnostic
cohort studies o the CRP, ESR, ecal calprotectin, or ecal lacto-
errin that met the ollowing inclusion criteria: (i) human stud-ies in adults that compare CRP, ESR, ecal calprotectin, or ecal
lactoerrin with conrmed diagnosis o IBD with IBS or healthy
control (HC) subjects; (ii) studies that utilize the enzyme-linked
immunosorbent assay or ecal calprotectin, not the point o care
testing; (iii) used Manning or Rome Criteria or IBS diagnosis;
and (iv) provided suffi cient data (studies must give medians and
either condence intervals or the median, interquartile ranges,
or ranges). I there were multiple papers published based on the
same or overlapping data sets, then only the paper with the high-
est number o subjects, the most detailed results, and the long-
est ollow-up time was included. No study size or language was
restricted. Any discrepancies in article selection were resolved byjoint reevaluation o the article by the reviewers and through con-
sensus with a senior reviewer (W.D.C.).
Tree authors (S.M., J.K., and A.G.) independently extracted
data. Te ollowing data were abstracted rom each study: (i) study
characteristics: authors, publication year, study site, and design;
(ii) patient characteristics: sex, age, race, IBD, and IBS criterion;
and (iii) test characteristics: type o assay, median values or CRP,
ESR, ecal calprotectin, and ecal lactoerrin. In cases o discord-
ance, a consensus was reached with the senior author (W.D.C.).
Study quality was assessed with the quality assessment or studies
o diagnostic accuracy (QUADAS) tool (17).
Statistical analysis
Te meta-analysis assumed that the logarithms o the biomark-
ers were normally distributed or the IBS, IBD, and HC groups.
Te means and s.d. values o biomarker logarithms were esti-
mated based on studies that gave medians and either condence
intervals or the median, interquartile ranges, or ranges. Age was
assumed to be normally distributed or all three groups, and all
studies were used to estimate the age distributions and gender
prevalence. Population-based estimates o IBS and IBD re-
quency (10% or IBS and (780,000+46,000)/320,000,000 or IBD)
were used to estimate prior probabilities or HCs, IBS, and IBD
(18,19). Bayes theorem was then applied to estimate the probabil-
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46
FUNC
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VOLUME 110 |MARCH 2015
Menees et al.
ities o being a HC, having IBS, or having IBD based on the given
values or the biomarkers (Table 1). Tis estimation assumed that
the values o the biomarkers, gender, and age were conditionally
independent given the health status o the patient. Heteroge-
neity among each subject group or the most useul biomark-ers was explored utilizing the inconsistency index (I2 statistic).
Heterogeneity was dened as I250%.
RESULTS
Systematic literature review identied 1,252 citations (Figure 1).
Afer cross-reerencing medical subject headings, detailed
evaluation identied 140 potentially relevant journal articles/
abstracts or CRP, ESR, ecal calprotectin, and ecal lactoerrin.
Ultimately, 67 ull manuscripts and abstracts were reviewed in
detail o which 12 studies (N=2,145: 1,059 IBD, 595 IBS, and 491
HC) ullled inclusion criteria and were included in the meta-
analysis. Details regarding the study populations enrolled, sam-ple size, CRP, ESR, ecal calprotectin, or ecal lactoerrin median
values with condence intervals or the median, interquartile
ranges, or ranges can be ound in (Table 2). Data on gender
were available in 11 out o 12 studies. Te IBD, IBS, and HC
cohorts were 52.7%, 29.9%, and 53.5% male, respectively. Te
mean age or the IBD, IBS, and HC cohorts was 40.7 (13.3),
40.0 (18.2), and 38.7 (13.8) years, respectively. Our analysis
ound that none o the biomarkers were able to accurately dis-
criminate patients with IBS rom HCs. However, some o the
biomarkers offered value in terms o discriminating IBD rom
IBS or HCs.
C-reactive protein
For the CRP analysis, 4 studies (2023) had suitable data (N=823;
465 IBD, 224 IBD, and 134 HC) (Table 2). Elevated CRP levels
were predictive o IBD (Figure 2). A level o 1.7 mg/dl has a
>52% predictive probability o IBD. Levels >2.7 mg/dl havemore than a 90% likelihood o IBD. In addition, the inverse also
appeared to be true. Low levels o CRP strongly argued against
the presence o IBD. A CRP o 0.5 predicted a 1% or lower like-
lihood o IBD. For IBS, the predictive probability o CRP rises
steadily to a 45.7% peak likelihood o IBS at 1.3 mg/dl, but then
gradually declines to
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Meta-Analysis of Biomarkers for Identifying IBS
259 IBS, and 238 HC) (Table 2). For IBD, as the level o ecal
calprotectin increases, so does the likelihood o IBD with the
maximal predictive value o 78.7% at 1,000/g (Figure 4). How-
ever, a patient with a level o
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Meta-Analysis of Biomarkers for Identifying IBS
Table2.
Continued
Author
(year)
Studypopula-
tion
Studysettin
g
Studysite
Numberof
patients
IBSDxcriteria
IBDcriteria
Testbrand
Median
values(CAL/LAC:
g/g,E
SR:mm/h,
CRP:
mg/dl)
CD
UC
IBD
IBS
HC
Oikonomou
etal.(21)
Patientswith
knownIBS/
IBD
Unclear
Greece
88
93
181
41
82
RomeIII
Clinical,
endoscopic,
radiological,
andhistologi-
calworkup,
basedon
standard
criteria
LaboratoryESR
andCRP
ESR,CRP
CD:17(255),17.5(1157)
UC:14
(266),7(1172)
IBS:17(726),4(08)
HC:11
(324),3(0.512)
Sidhuetal.
(31)
Consecutive
patientswith
knownIBD/
IBS
Outpatient
clinic
UK
104
126
130
137
98
RomeIIfordiar-
rheapredomi-
nantIBS
Established
diagnosisbyGI
LAC:SCHEBO
BIOTECHUK
andtechlab,
Blacksburg,VA
CD:4(13)
U
C:6.6(42)
IBS:0(1.4)
HC:0.5(2)
Tibbleetal.
(20)
Consecu-
tivepatients
referredfor
opinionasto
whetherthey
hadIBSorIBD
GIoutpatient
clinic
US
31
0
31
159
0
Manning
Standard
clinical,
radiological,
endoscopic
andhistologi-
calcriteria
LaboratoryESR
andCRP
ESR
CD
:23(1045),
10(330)
IBS:6(68),3(37)
Wassell
etal.(30)
Patients
diagnosed
IBSorCrohns
GIclinic
UK
25
0
25
25
27
RomeII
Provenhisto-
logicdiagnosis
CAL:Calprotech
LTD.London,
UK
CD:22
9.6(6.51,1966)
IBS:
20.5(6.587.3)
HC:
9.3(6.563.8)
CAL,fecalcalprotectin;CD,Crohnsdisease;CRP,C-reactiveprotein;Dx,diagnosis;ELISA,enzyme
-linkedimmunosorbentassay;ESR,erythrocytese
dimentationrate;GI,gastrointestinal;HC,healthycontrol;IBD,inflam-
matoryboweldisease;IBS,irritablebowelsyndro
me;LAC,fecallactoferrin;N/A,notavailable;SBFT,smallbowelfollow-through;UC,ulcerativecolitis
.
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50
FUNC
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Menees et al.
and details regarding whether the reerence standard was inde-pendent o the index test (2023,2831).
DISCUSSION
Te symptoms o IBS, including abdominal pain/discomort
and altered bowel habits, can overlap with a number o organic
diseases. Te identication o noninvasive tests that can aid in
a condent, cost-effective diagnosis o IBS is vital to primary
care providers and specialists alike. Despite the relatively low
likelihood, patients and providers remain concerned about
the possibility o IBD in patients with typical IBS symptoms.
Our meta-analysis o 12 studies ound that none o the serumand ecal biomarkers evaluated, including CRP, ESR, ecal
calprotectin, and ecal lactoerrin, accurately identied patients
with IBS vs. IBD patients or HCs. However, both CRP and
ecal calprotectin appeared to be clinically useul in ruling
out IBD. On the other hand, the commonly ordered serum
biomarker, ESR, provided no value in distinguishing between
IBD and IBS patients. Te other ecal biomarker, ecal lacto-
errin, was more predictive o IBS rather than IBD, but had
signicant overlap between IBD and IBS. Tis renders it clini-
cally unhelpul in trying to rule out IBD in patients with IBS
symptoms.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0.1
0
0.2
0
0.3
0
0.4
0
0.5
0
0.6
0
0.7
0
0.8
0
0.9
0
1.0
0
1.1
0
1.2
0
1.3
0
CRP level, mg/dl
1.4
0
1.5
0
1.6
0
1.7
0
1.8
0
1.9
0
2.0
0
2.1
0
2.2
0
2.3
0
2.4
0
2.5
0
2.6
0
2.7
0
Percent,%
CRP
0.1 89.9 9.8
9.9
11.2
13.6
16.8
20.8
25.8
30.235.0
39.3
42.7
89.8
88.4
85.8
82.1
77.4
71.7
65.157.9
50.2
42.435.0
28.1
17.0
12.9
9.6
7.1
5.2
3.8
2.8
2.0
1.5
1.1
0.8
0.6
0.4
22.1
0.2
0.3
0.4
0.5
0.6
0.7
0.80.9
1.0
1.1P (Control)
P (IBS)
P (IBD)1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
2.5
2.6
2.7
Percentlikelihood
HC
Percentlikelihood
IBS
Percentlikelihood
IBD
44.9
45.7
45.2
43.5
40.9
37.6
34.1
30.5
27.0
23.7
20.6
17.9
15.5
13.4
11.6
10.0 89.6
87.8
85.8
83.4
80.6
77.4
73.6
69.2
64.3
58.8
52.7
46.2
39.5
32.7
26.2
20.114.9
10.6
7.24.7
3.0
1.8
1.1
0.6
0.4
0.3
0.2
Figure 2. CRP predictive probability of being a healthy control, or having IBS or IBD. The line graph is a graphical representation of the table. The dottedline represents the following: at a CRP level of 0.2 mg/dl, a person has a 0.3% probability of IBD, a 9.9% probability of IBS, and 89.9% probability of being
a healthy control. CRP, C-reactive protein; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome.
20%
10%
100%
0%
40%
30%
50%
Percent,%
70%
60%
80%
90%
10 20 30 40 50 60 70 80 90 100
ESR, mm/h
110 110 130 140 150 160 170 180 190 200
P (Control)
ESRPercent
likelihoodHC
Percentlikelihood
IBS
Percentlikelihood
IBD
10 89.3
93.1
95.8
97.1
97.9
98.3
98.5
98.698.7
98.8
98.898.898.8
98.7
98.7
98.7
98.7
98.6
98.6
98.5
10.4 0.3
0.3
0.4
0.5
0.5
0.6
0.7
0.70.8
0.8
0.91.01.0
1.1
1.1
1.2
1.2
1.3
1.3
1.4
6.5
3.8
2.4
1.6
1.1
0.8
0.60.5
0.4
0.30.20.2
0.2
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0.1
0.1
0.1
0.1
0.1
20
30
40
50
60
70
8090
100
110120130
140
150
160
170
180
190
200
P (IBS)
P (IBD)
Figure 3. Fecal calprotectin predictive probability of being a healthy control, or having IBS or IBD. The line graph is a graphical representation of the table.
The dotted line represents the following: at a fecal calprotectin level of 40g/g, a person has a 1% probability of IBD, a 14.9% probability of IBS, and
84.1% probability of being a healthy control. IBD, inflammatory bowel disease; IBS, irritable bowel syndrome.
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Meta-Analysis of Biomarkers for Identifying IBS
Fecal calprotectin is increasingly being utilized as a screen-
ing test or IBD and as an index o disease activity. Numerous
controlled studies in IBD patients have been perormed yielding
varying sensitivities and specicities (14,22,23,2528,30,3638).Te meta-analyses o ecal calprotectin by both von Roon et al.
(39) and van Rheenen et al.(40) ound an overall sensitivity and
specicity or IBD o >90%. In addition, using the area under the
receiver operating characteristic curve, the authors ound that
100g/g had better diagnostic precision or IBD compared with
50g/g. Although ruling in IBD was not our primary aim, we
did nd that patients with a ecal calprotectin o 100g/g had
a 3% predictive probability o IBD. Clinicians are also utilizing
ecal calprotectin or assessing IBD clinical activity. Sipponen
et al. (41) ound that a level o >200g/g correlates best with
endoscopically active disease.
O the serum biomarkers evaluated, our analysis ound that
CRP at a level o 1 mg/dl is universally considered abnormal.It is important to acknowledge that patients with IBD can present
with normal CRP levels (3234). An elevated CRP is more likely
to be present in patients with Crohns disease than ulcerative coli-
tis (3335). Henriksen et al.(33) ound a CRP o 10 mg/l in 25%
o Crohns disease patients and 71% o ulcerative colitis patients in
a prospective population-based study. Unortunately, no inorma-
tion is available regarding the absolute CRP values among patients
with a CRP o
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4
Meta-Analysis of Biomarkers for Identifying IBS
numerical values o these biomarkers to a log scale and the need to
use crude methods to estimate the means and s.d. values. Related
to this, it is important to acknowledge that our analysis summary
o data derived rom varying clinical and geographical popula-
tions. In addition, the cited studies do not stratiy their biomarker
results by age and gender, and hence we are unable to account or
these dependencies in our biomarker models, specically in reer-
ence to ESR. Finally, because o the nature o the available data, we
are limited in speciying the exact symptom complex that warrants
screening as the included studies utilized either Rome or Manning
IBS criteria, but did not give urther details regarding IBS subtypes.
In summary, CRP and ecal calprotectin might provide non-
invasive means by which to screen or IBD in patients with IBS
symptoms. Based upon these results, it may be reasonable or cli-
nicians to consider ordering CRP or ecal calprotectin to improve
their condence in making a diagnosis o IBS. ESR is o no value
in discriminating between IBD and IBS. Finally, too little data are
available to make a judgment on the utility o ecal lactoerrin in
excluding IBD. Prospective studies to evaluate the clinical utilityand cost effectiveness o adding CRP or ecal calprotectin to the
evaluation o patients with suspected IBS in different populations
would be o considerable interest.
CONFLICT OF INTEREST
Guarantor of the article:William D. Chey, MD, AGAF, FACG, FACP.
Specic author contributions:S.B.M., and W.D.C. conceived
and drafed the study. S.B.M., J.K., and A.G. collected all data.
S.B.M.,W.D.C., and C.P. analyzed and interpreted data. C.P. pro-
vided statistical advice and support. S.B.M. drafed the manuscript.
All authors commented on drafs o the paper. All authors have
approved the nal draf o the manuscript.Financial support:Tis study was supported by Division o
Gastroenterology, University o Michigan Health System.
Potential competing interests:William D. Chey is a consultant or
Salix Pharmaceuticals. Stacy Menees, Corey Powell, Jacob Kurlander,
and Akash Goel declare no conict o interest.
Study Highlights
WHAT IS CURRENT KNOWLEDGE
Many clinicians consider irritable bowel syndrome (IBS) adiagnosis of exclusion.
A number of commercially available biomarkers have proveduseful in the diagnosis and follow-up for inflammatory bowel
disease (IBD).
Currently, no inflammatory routine biomarkers are routinelyrecommended as part of the evaluation in the patients with
IBS symptoms.
WHAT IS NEW HERE
None of the biomarkers reliably distinguished between IBSand healthy controls.
C-reactive protein (CRP) and fecal calprotectin at or below 0.5and 40g/g, respectively, can exclude IBD in patients with IBS.
Erythrocyte sedimentation rate (ESR) and fecal lactoferrinwere clinically unhelpful.
Our study would seem to provide indirect support or the
concept o low-grade inammation in a subset o IBS patients
(3236). In our meta-analysis population, ecal calprotectin levels o
>100g/g were associated with a more than 15% likelihood o IBS.
Te peak predictive probability o IBS was a ecal calprotectin o
280g/g with an 18.8% predictive probability o IBS. At this level,
there was also a 17.1% predictive probability o IBD. Tese ndings
suggest that ecal calprotectin below the stated threshold effectively
rules out IBD; however, many patients with elevated ecal calpro-
tectin levels will ultimately be assigned the diagnosis o IBS rather
than IBD. In other words, the negative predictive value o ecal
calprotectin is high but the positive predictive value o this test is
poor. Tis same concept would also be applicable or CRP. Tus,
CRP and ecal calprotectin, like alarm eatures in general, may be
useul to identiy patients who are at greater risk o organic disease,
and thus should undergo a more detailed structural evaluation.
ESR and ecal lactoerrin were least helpul in discriminating
between IBS and IBD. All levels o ESR had a 10 mm/h in differentiating between organic and nonorganic
intestinal disease. Other studies have demonstrated a sensitivity and
specicity ranging rom 56 to 78% and 75 to 96% or an elevated
ESR (>10 and 15 mm/h) in differentiating IBD rom IBS (23,32).
Based on our data, ESR should not be used as a screening test or
IBD in patients with IBS symptoms. Te eligible data assessing ecal
lactoerrin or IBD and IBS cohorts were limited to two studies. Tis
small sample size limited our ability to draw condent conclusionsregarding the value o ecal lactoerrin in ruling out IBD in patients
with IBS symptoms. A recent meta-analysis o 7 studies or ecal
lactoerrin demonstrated a pooled sensitivity o 0.78 (95% con-
dence interval: 0.750.82) and a specicity o 0.94 (95% condence
interval: 0.910.96) in differentiating IBD rom IBS. However, this
meta-analysis utilized studies with varying test cutoffs and mixed
populations o both adults and children (43). It is interesting that in
our analysis, high levels o ecal lactoerrin level were more predic-
tive o IBS than IBD. Tat being said, the considerable overlap in
positive results or IBS and IBD or all o ecal lactoerrin under-
mines its value as a test to identiy patients with IBS.
A strength o our study was the inclusion o only prospective
studies that utilized dened criteria or the diagnosis o IBD andIBS. Our study is novel in trying to identiy numerical thresholds
or commonly available serum and ecal biomarkers to exclude
IBD in patients with IBS symptoms. Our study also has a number
o weaknesses. Because o our statistical methods, we were limited
in utilizing only data that were reported as medians with con-
dence intervals, interquartile ranges, or ranges or the median.
Tere were several studies that presented data as the mean with s.d.
that could not be included in our analysis (14,37,38,42,4451). Tis
particularly limited our ability to assess the utility o ecal lactoer-
rin. Another by-product o our statistical approach was the intro-
duction o heterogeneity as a consequence o transorming the
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54
FUNC
TIONAL
GIDISORD
ERS
Menees et al.
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