RESEARCH

RESEARCH Pre-endoscopy serological testing for coeliac disease:
evaluation of a clinical decision tool Andrew D Hopper, gastroenterology specialist registrar, 1 Simon S Cross, reader in pathology and honorary consultant in pathology , 3 David P Hurlstone, consultant gastroenterologist, 1 Mark E McAlindon, consultant gastroenterologist, 1 Alan J Lobo, consultant gastroenterologist, 1 Marios Hadjivassiliou, consultant neurologist , 4 Marion E Sloan, general practitioner, 5 Simon Dixon, senior lecturer in health economics, 2 David S Sanders, consultant gastroenterologist 1 ABSTRACT Objective To determine an effective diagnostic method of
detecting all cases of coeliac disease in patients referred
for gastroscopy without performing routine duodenal
biopsy. Design An initial retrospective cohort of patients
attending for gastroscopy was analysed to derive a
clinical decision tool that could increase the detection of
coeliac disease without performing routine duodenal
biopsy. The tool incorporated serology (measuring
antibodies to tissue transglutaminase) and stratifying
patients according to their referral symptoms (patients
were classified as having a high risk or low risk of coeliac disease). The decision tool was then tested on a
second cohort of patients attending for gastroscopy. In
the second cohort all patients had a routine duodenal
biopsy and serology performed. Setting Teaching hospital in Sheffield. Participants 2000 consecutive adult patients referred for
gastroscopy recruited prospectively. Main outcome measure Evaluation of a clinical decision
tool using patients referral symptoms, tissue transglutaminase antibody results, and duodenal biopsy
results. Results No cases of coeliac disease were missed by the
pre-endoscopy testing algorithm. The prevalence of
coeliac disease in patients attending for endoscopy was
3.9% (77/2000, 95% confidence interval 3.1% to 4.8%).
The prevalence in the high risk and low risk groups was
9.6% (71/739, 7.7% to 12.0%) and 0.5% (6/1261, 0.2%
to 1.0%). The prevalence of coeliac disease in patients
who were negative for tissue transglutaminase antibody
was 0.4% (7/2000). The sensitivity, specificity, positive
predictive value, and negative predictive value for a
positive antibody result to diagnose coeliac disease was
90.9%, 90.9%, 28.6%, and 99.6%, respectively.
Evaluation of the clinical decision tool gave a sensitivity,
specificity, positive predictive value, and negative
predictive value of 100%, 60.8%, 9.3%, and 100%,
respectively. Conclusions Pre-endoscopy serological testing in
combination with biopsy of high risk cases detected all cases of coeliac disease. The use of this decision tool may
enable the endoscopist to target patients who need a
duodenal biopsy. INTRODUCTION Coeliac disease is a common chronic inflammatory
bowel condition encountered by doctors. Serological
screening in healthy volunteers around the world has
estimated the prevalence at 0.5-1.0%. 1-7 A recent meta- analysis indicated that the ratio of known to undiag-
nosed cases of coeliac disease was 1:7. 6 This suggests a failure in case finding for this disease. 6 8 9 The median age for diagnosis of coeliac disease in adults is between
the fourth and fifth decade. 10-12 The median delay in diagnosis ranges from 4.9 to 11 years. 10-12 Patients with adult coeliac disease usually present with diarrhoea, weight loss, or symptoms that suggest
malabsorption or anaemia. This type of coeliac disease
is known as the classic (typical) form. The disease may
not always be recognised however because of the insi-
dious nature of its presentation, and many visits to hos-
pital may be needed before diagnosis. 13 Patients can also have the silent or atypical form of disease. These
patients may present with non-specific abdominal
pain, 14 oesophageal reflux, 15 16 osteoporosis, crypto- genic hypertransaminasaemia, insulin dependent dia-
betes mellitus, 17 or neurological symptoms. 5 6 18 Untreated coeliac disease is associated with high mor-
bidity and increased mortality. 19 20 Although the presentation of patients with coeliac disease may be protean, serological markers are a
cheap and non-invasive method for clinicians in pri-
mary care and secondary care to identify patients
with this disease. The positive and negative predictive
value of combining the measurement of IgA antibodies
to tissue transglutaminase and IgA endomysial anti-
bodies has been reported to be greater than 96%. 21 Current serological testing for coeliac disease involves
the use of one or both of these antibodies, depending
on local practice. 22 However, the internationally accepted gold standard diagnostic test for coeliac dis- ease is the demonstration of villous atrophy on a duo-
denal biopsy. 23 24 Such biopsies are graded 1 Department of Gastroenterology, Royal Hallamshire Hospital,
Sheffield 2 Health Economics and Decision Science (HEDS), University of
Sheffield, Sheffield 3 Section of Oncology and Pathology, Division of Genomic
Medicine, University of Sheffield
Medical School, Sheffield 4 Department of Neurology, Royal Hallamshire Hospital 5 Surgery, 29 Blackstock Road, Sheffield S14 1AB Correspondence to: A D Hopper, 15
Nairn Street, Sheffield S10 1UL
andydhopper@aol.com doi: 10.1136/bmj.39133.668681.BE BMJ | ONLINE FIRST | bmj.com page 1 of 5 Cite this article as: BMJ, doi:10.1136/bmj.39133.668681.BE (published 23 March 2007) Copyright 2007 BMJ Publishing Group Ltd histologically according to the modified Marsh criteria
and reflect the pathological progression (histologi-
cally) towards coeliac disease. Marsh grade 0 is normal
duodenal mucosa, grade 1 is the presence of a raised
intraepithelial lymphocyte count, and grade 2 is raised
intraepithelial lymphocytes and crypt hyperplasia.
Marsh grade 1 and grade 2 lesions are considered to
be early changes in patients who are likely to develop
coeliac disease. Marsh grade 3 is raised intraepithelial
lymphocytes and crypt hyperplasia with progression
of the inflammation to villous atrophy. Marsh grade 3
is subdivided into Marsh 3a partial villous atrophy, 3b subtotal villous atrophy, and 3ctotal villous atrophy. 25 26 The presence of a Marsh 3 lesion (villous atrophy) on duodenal biopsy together with a positive
antibody profile is currently internationally accepted
as coeliac disease, although antibody negative coeliac
disease does exist. 23 24 This may occur if patients are IgA deficient (and cannot generate IgA tissue transglu-
taminase antibodies or endomysial antibodies), but it
can also happen in patients who have normal total IgA
immunoglobulin concentrations. Such patients are
classed as having coeliac disease if they have villous
atrophy on duodenal biopsy and the appropriate
human leucocyte antigen pattern (HLA DQ2 or HLA
DQ8). They should also have symptoms suggestive of
coeliac disease that respond to a gluten-free diet and
show a corresponding improvement in histology. 23 24 A previous European multicentre series reported that
antibody negative coeliac disease accounted for 6.4%
(8 of 126) of all cases of coeliac disease. 27 A duodenal biopsy can be taken from any patient referred for gastroscopy. We and others have reported
that 13.6% of patients later diagnosed with coeliac dis-
ease had had a gastroscopy within the previous five
years but no duodenal biopsy had been taken. 10 This may be because of sole reliance on endoscopic features
for recognising coeliac disease, even though such fea-
tures are only 50-87.5% sensitive for detecting this
disease. 28 Higher levels of detection are thought to cor- relate with endoscopic experience and the severity of
villous atrophy. In addition, inter-rater reliability is
poor. 28 Because of the limitations of endoscopy, anti- body negative coeliac disease, and delays in diagnosis,
many centres around the world suggest or recommend
routine duodenal biopsy. In clinical practice, however,
this policy varies greatly, and reported rates of duode-
nal biopsy range from 30.9% to 74%. 29-32 The reported prevalence of coeliac disease when taking a routine
duodenal biopsy ranges from 1.0% to 5.2%. 33-42 How- ever, prevalence depends greatly on the population
studied. Since the advent of tissue transglutaminase
and endomysial antibodies, the practice of routine
duodenal biopsy has not been fully evaluated in the
context of referrals from primary care. We devised and evaluated a clinical decision tool that used a combination of pre-endoscopy serological
testing (for tissue transglutaminase antibodies) and
assessment of symptoms to identify patients with coe-
liac disease. This decision tool might help increase the
detection of coeliac disease in patients attending for gastroscopy without the need to perform routine duo-
denal biopsy. METHODS Retrospective analysis and creation of a clinical decision
tool
From January 2003 to January 2004 our centre per-
formed 5979 gastroscopies. We analysed the data
from 1464 unselected patients who had both a gastro-
scopy and duodenal biopsy. On the basis of this retro-
spective data, the prevalence of new cases of coeliac
disease identified in patients referred for endoscopy
was 4.2% (61 of 1464). We assessed the indications for referral in these unse- lected patients and whether the biopsy findings indi-
cated coeliac disease. We categorised patients with
indications of weight loss, anaemia, or diarrhoea as
having a high risk for coeliac disease. In routine clin- ical practice, such patients should have a duodenal
biopsy taken as per British Society of Gastroenterology
guidelines. 43 44 Anaemia was defined as a haemoglobin concentration of less than 120 g/l in female patients
and less than 130 g/l in male patients; diarrhoea was
defined as a bowel frequency of more than three times
a day (both definitions as suggested by British Society
of Gastroenterology guidelines). 43 44 Patients were deemed as having lost weight if this was stipulated in
the referral letter from their general practitioner and
confirmed by the patient at gastroscopy. The remain-
ing patients (whose symptoms were atypical for coeliac
disease) were categorised as having a low risk. Symp- toms classified as low risk include all other indications
for gastroscopy, such as abdominal pain, reflux, dys-
pepsia, vomiting or nausea, and chest pain. Of the 1464
patients analysed who had gastroscopy and a duodenal
biopsy, 1085 (74.1%) were high risk and 379 (25.9%)
were low risk. In this retrospective group, tissue transglutaminase antibody titre was part of the antibody profile per-
formed in 109 patients. Eighty nine of the 109 patients
(81.7%) were at high risk and 20 (18.3%) were at low
risk of coeliac disease. Tissue transglutaminase anti-
body testing was performed in these patients because
the investigating doctor considered coeliac disease to
be a possible cause of their symptoms before gastro-
scopy. Eighteen of the 109 patients (16.5%) had coeliac
disease, two of whom were negative for tissue transglu-
taminase antibodies. Nineteen of the 109 patients were
positive for tissue transglutaminase antibodies 16 had coeliac disease but three had a normal duodenal
biopsy. The sensitivity, specificity, positive predictive
value, and negative predictive value for tissue transglu-
taminase antibodies in the detection of coeliac disease
were 94.1%, 96.7%, 84.2%, and 97.8%. The two anti-
body negative patients with coeliac disease both had
high risk referral symptoms. When we combined the
referral indication of high risk with positive tissue
transglutaminase antibody results the sensitivity for
diagnosing coeliac disease was 100% (95% confidence
interval 82.4% to 100%). RESEARCH page 2 of 5 BMJ | ONLINE FIRST | bmj.com On the basis of these data, we devised a clinical deci- sion tool that might obviate the need to perform rou-
tine duodenal biopsy but still detect unrecognised
coeliac disease in patients referred for gastroscopy.
We proposed that combining pre-endoscopy serologi-
cal testing (using tissue transglutaminase antibodies)
with identification of high risk patients would allow
us to target patients who need a duodenal biopsy
(fig 1). Prospective evaluation of clinical decision tool
We recruited patients from a single endoscopy depart-
ment at the Royal Hallamshire Hospital, Sheffield.
This centre serves a population of around 250 000
and carries out 5000-6000 gastroscopies annually.
The patients had been referred by their general practi-
tioner for either gastroscopy or a consultation and
gastroscopy. A single endoscopist recruited partici-
pants for the evaluation study (second cohort) during a
26 month period (January 2004 to April 2006). The
department of medical gastroenterology currently per-
forms duodenal biopsy as part of the endoscopic exam-
ination. We classified all patients according to the
referral information into high risk and low risk groups.
At gastroscopy, we confirmed the symptoms described
in the referral letter by questioning the patient directly
and obtained patient consent. Quadrantic biopsies
were taken from the second part of the duodenum in
all patients. We also took a blood sample which was
analysed for IgA tissue transglutaminase antibodies.
We excluded patients if they had a known diagnosis
of coeliac disease, coagulopathy (international normal-
ised ratio >1.3 or platelets <80

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