Transcript Endoscopy Audit - ACB South Western and Wessex Region

New Tests in
Gastroenterology
Stephen Bridger
ACB Meeting 10/11/2005
Gastroenterology
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Too Busy
– Too Many patients
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IBS 14 - 24% of adult population, + 28% of referrals to GI
clinics
– Too Many Investigations
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Non Specific nature of GI symptoms
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Doubling of endoscopy workload in last 10 yrs
Even alarm symptoms such as rectal bleeding common (1 in 7
adults/week) + poorly predictive of significant GI pathology
Unable to predict which of our chronic patients
will relapse and when.
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“Would you mind very much if I went in before
you? You’ve only a sore throat and I’ve
diarrhoea”
Lundberg JO et al. (2005) Technology Insight: calprotectin, lactoferrin and nitric oxide as novel markers of
inflammatory bowel disease
Nat Clin Pract Gastroenterol Hepatol 2: 96–102 doi:10.1038/ncpgasthep0094
Calprotectin

35 KDa Calcium and Zinc binding protein found
in neutrophils, monocytes, and macrophages
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Up to 60% of the total cytosolic protein content of
neutrophils

First Described in 1980
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Initially called L1 protein
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Antimicrobial and Anti-tumour activity

reduces local zinc concentrations, and inhibits zinc
dependent metalloproteinases
Clinical Use
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Resists metabolic degradation
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measured in stool, plasma, CSF, sputum, amniotic
fluid
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Stool samples can be sent by post, then frozen and
batch analysed
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Approx £10 per test
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Upper limit of normal in stool is 10mg/l
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As little as 5gm stool sample required
Clinical Uses
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extensively validated, showing consistent
abnormalities in patients with IBD, colorectal
carcinoma, and nonsteroidal enteropathy
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Proposed as a useful outpatient screening test for
organic small bowel or colorectal pathology. May
be particularly useful in children.

Proposed as an IBD monitoring test, can predict
steroid refractory disease, or which “well patients”
are likely to relapse. Potential for monitoring the
efficacy of new therapeutic regimes.
General Background
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Levels relatively unaffected by GI bleeding
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need > 100mls of blood per day to increase
calprotectin level by 6mg/l
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In active Crohn’s disease, levels of calprotectin up
to 40,000 mg/l reported
Guidelines for the investigation of
chronic diarrhoea, Gut 2003
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“Stool markers of gastrointestinal
inflammation such as lactoferrin and, more
recently, calprotectin, are of considerable
research interest but, as yet, these have not
been introduced into clinical practice.”
A simple method for assessing intestinal
inflammation in Crohn's disease
Tibble et al Gut 2000
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22 patients: fecal calprotectin compared
with 4 day 111Indium White Cells
– Good correlation (r = 0.8 , P<0.0001)
116 patients with known Crohn’s disease,
calprotectin was compared with healthy
controls
 220 consecutive patients attending a GI
clinic, 31 newly diagnosed Crohn’s disease,
159 patients with IBS...
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Calprotectin: Crohn’s versus Controls
Calprotectin compared with
CRP
Use of surrogate markers of inflammation and
Rome criteria to distinguish organic from
nonorganic intestinal disease
Tibble et al Gastroenterology 2002
Prospective study: 602 new GI referrals
 4 Gastroenterologists blinded to the results
of calprotectin and permeability, other
investigations determined by Physicians
 263 patients diagnosed with organic disease
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Referral Symptoms
Calprotectin Levels in the
Different Diagnostic Groups
Sensitivity/Specificity for Organic
and Non-Organic Disease
Sensitivity
Specificity
Calprotecin >
10mg/L
Positive Rome
Criteria
CRP > 5.0 mg/L
89
79
85
71
50
81
ESR > 10
mm/Hr
58
72
Odds Ratios for Organic and
Non-organic Disease
Calprotecin >
10mg/L
CRP > 5mg/L
ESR >
10mm/Hr
L/R > 0.05
+’ve Rome
Criteria
OR
PPV
NPV
27.8
(17.6 – 43.7)
4.2
(2.9 – 6.1)
3.2
(2.2 – 4.6)
8.9
(5.8 – 14)
13.3
(8.9 – 20)
0.76
0.89
.67
0.68
0.62
0.69
0.56
0.89
0.86
0.69
Diagnostic accuracy of fecal calprotectin in
distinguishing organic causes of chronic
diarrhoea from IBS: A prospective study in
adults and children.
Carroccio et al Clin Chem Jun 2003
Prospective study 120 patients
 Raised Calprotecin levels predicted pts with
IBD with 100% sensitivity and 95%
specificity
 Diagnostic accuracy higher in children
 Coeliac disease was the commonest cause
of false negatives
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Fecal calprotectin - a useful screening test for
inflammation of the colon in children.
Fagerberg et al DDW 2003
36 children : calprotectin prior to
colonoscopy
 22 of the children had colitis on Hxpath +
endoscopic criteria:
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– Mean calprotectin 349 (15.4 - 1860 mg/L)
Sensitivity & Positive predictive value 95%
 Specificity of 93%
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Fecal Calprotectin as an aid to Diagnosis in
intestinal inflammation
Dolwani et al DDW 2003
65 patients with abdo pain + diarrhoea
 All referred for Barium follow through
 15 false negatives: 6 IBD, 4 IBS, 5
uncertain

Ba FT Normal Ba FT abnormal
Calprotectin < 60
33
1
Calprotectin > 60
15
16
Fecal Calprotectin in steroid dependent Colitis.
An indicator of clinical response
Atkinson DDW 2003
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27 patients with steroid dependent colitis in
remission
Calprotectin checked at 0, 8 and 16 weeks
steroids reduced at 2 weekly intervals until relapse
or cessation
Mean Calprotectin at Time Zero was 6 x higher in
those patients who Relapsed (P = 0.0009)
“CPT may differentiate between pts with merely
symptomatic response and those with genuine mucosal
healing- failure to lower CPT sufficiently may indicate the
need for a trial of a different therapy”
Surrogate markers of intestinal inflammation
are predictive of relapse in patients with
inflammatory bowel disease
Gastroenterology 2000;119:15-22
Subclinical intestinal inflammation: An
inherited abnormality in Crohn’s
disease relatives?
Gastroenterology June 2003
Effect of Pentavac and MMR
vaccination on the intestine
Gut 2002 816-17
109 consecutive infants attending an Iceland
Vaccination clinic had fecal calpro taken 1
week prior and 2 and 4 weeks after
Pentavac (12 months) and MMR (18
months)
 No differences at any time of study
 “MMR very unlikely to cause ‘autistic
enterocolitis’”
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Calprotectin versus FOB in Bowel
Cancer
FOB screening in asymptomatic patients
has reduced bowel ca mortality by 15-33%
 Detection threshold about 2-4 mls of
blood/100g stool but tumours bleed
intermittently and polyps may not bleed at
all
 Sensitivity of FOB may be as low as 26%

Faecal Calprotectin and FOB tests in the
diagnosis of colorectal carcinoma and
adenoma. Gut 2001 49(3):402-8
 3 FOBs and 1 stool calprotectin sample
 Three groups
– 96 Controls (healthy volunteers)
– 62 consecutive patients with newly diagnosed
bowel cancer
– 233 consecutive patients referred for
colonoscopy for polyp follow up, cancer
surveillance, anaemia
Calprotectin vs FOB
Dukes n
Stage
median range
A
10
62.5
7-933
B
24
115
2-3770
C
14
62
D
14
132
1.5314
10.5 3388
+’ve by
+’ve
calprotectin by
FOB
90
88
20
46
86
100
100
71
Faecal Calprotectin in the Different
Diagnostic Groups
Fecal Calprotectin levels in a high risk
population for colorectal neoplasia
Kronberg et al Gut 2000 (46) 795 -800
Calprotectin and Cancer
Conclusions

Calprotectin has significant advantages over
guaiac based FOB testing
– Higher sensitivity for colorectal ca
– More likely to detect patients with Dukes A + B
– More likely to detect patients with rectal and
right sided tumours
– Single test rather than 3 samples
– No dietary restrictions
Conclusions 2
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Sensitivity >95% for detecting patients with IBD
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Failure to lower CPT predicts those patients with steroid
refractory disease (even if the patient has had a good
symptomatic response to steroids)
Asymptomatic patients with IBD with CPT > 50mg/l have
a 90% probability of relapse in the next 12 months
CPT reduction in IBD treated patients appears to correlate
with endoscopic mucosal healing
CPT levels much more clinically useful in IBD than any of
the currently used systemic immune tests (CRP, ESR, Igs,
Plts)
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The Future?
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GI OPD screening
– Organic versus non-organic
– Investigate versus observe
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Population based bowel cancer screening
– Selected high risk groups
IBD monitoring
 Availability ?
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