Celiac

Issue date: May 2009
Coeliac disease
Recognition and assessment of coeliac disease
NICE clinical guideline 86

Developed by the Centre for Clinical Practice at NICE
NICE clinical guideline 86

Coeliac disease: recognition and assessment of coeliac disease
Ordering information
You can download the following documents from www.nice.org.uk/CG86
The full guideline (this document) all the recommendations, details of how
they were developed, and reviews of the evidence they were based on.
A quick reference guide a summary of the recommendations for
healthcare professionals.
Understanding NICE guidance a summary for patients and carers.
For printed copies of the quick reference guide or Understanding NICE
guidance, phone NICE publications on 0845 003 7783 or email
[email protected] and quote:
N1859 (quick reference guide)
N1860 (Understanding NICE guidance).
NICE clinical guidelines are recommendations about the treatment and care
of people with specific diseases and conditions in the NHS in England and
Wales.
This guidance represents the view of NICE, which was arrived at after careful
consideration of the evidence available. Healthcare professionals are
expected to take it fully into account when exercising their clinical judgement.
However, the guidance does not override the individual responsibility of
healthcare professionals to make decisions appropriate to the circumstances
of the individual patient, in consultation with the patient and/or guardian or
carer, and informed by the summary of product characteristics of any drugs
they are considering.
Implementation of this guidance is the responsibility of local commissioners
and/or providers. Commissioners and providers are reminded that it is their
responsibility to implement the guidance, in their local context, in light of their
duties to avoid unlawful discrimination and to have regard to promoting
equality of opportunity. Nothing in this guidance should be interpreted in a way
that would be inconsistent with compliance with those duties.
National Institute for Health and Clinical Excellence
MidCity Place
71 High Holborn
London WC1V 6NA
www.nice.org.uk
National Institute for Health and Clinical Excellence, 2009. All rights reserved. This material
may be freely reproduced for educational and not-for-profit purposes. No reproduction by or
for commercial organisations, or for commercial purposes, is allowed without the express
written permission of NICE.
Contents
A
a)
Disclaimer........................................................................................4
b)
Foreword..........................................................................................5
c)
Patient-centred care.......................................................................7
d) 1
Summary..........................................................................................9
B 1.1 Recommendations..............................................................................9
C 1.2 Care pathway....................................................................................14
D 1.3 Overview............................................................................................18
e) 2
Evidence review............................................................................20
E 2.1 Introduction........................................................................................20
F 2.2 Prevalence of coeliac disease...........................................................21
G 2.3 The possible long-term consequences of undiagnosed coeliac
disease.............................................................................................23
H 2.4 Signs and symptoms of coeliac disease and coexisting conditions
with coeliac disease..........................................................................26
I 2.5 Serological tests in the diagnostic process for coeliac disease........37
J 2.6 Research recommendations.............................................................59
f) 3
References, glossary and abbreviations...................................61
K 3.1 References........................................................................................61
L 3.2 Glossary............................................................................................71
M 3.3 Abbreviations.....................................................................................74
g) 4
Methods.........................................................................................74
N 4.1 Aim and scope of the guideline.........................................................74
O 4.2 Development methods......................................................................74
h) 5
Contributors..................................................................................79
P 5.1 The Guideline Development Group...................................................79
Q 5.2 Declarations.......................................................................................86
The appendices are available as separate files.

Appendix 6.1
Scope
Appendix 6.2
Key clinical questions and protocols
Appendix 6.3
ROC curves and forest plots
Appendix 6.4
Search strategies
Appendix 6.5
Health economics evidence and evidence tables
Appendix 6.6
Evidence tables
NICE clinical guideline 86 Coeliac disease
Disclaimer
NICE clinical guidelines are recommendations about the treatment and care
of people with specific diseases and conditions in the NHS in England and
Wales.
This guidance represents the view of NICE, which was arrived at after careful
consideration of the evidence available. Healthcare professionals are
expected to take it fully into account when exercising their clinical judgement.
However, the guidance does not override the individual responsibility of
healthcare professionals to make decisions appropriate to the circumstances
of the individual patient, in consultation with the patient and/or guardian or
carer, and informed by the summary of product characteristics of any drugs
they are considering.
Implementation of this guidance is the responsibility of local commissioners
and/or providers. Commissioners and providers are reminded that it is their
responsibility to implement the guidance, in their local context, in light of their
duties to avoid unlawful discrimination and to have regard to promoting
equality of opportunity. Nothing in this guidance should be interpreted in a way
that would be inconsistent with compliance with those duties.
Foreword
Coeliac disease is believed to be present in up to 1 in 100 of the population
although only about 1015% of people with the condition are clinically
diagnosed. Many of the remainder may be well, but a significant minority will
have chronic problems such as lethargy, gastrointestinal symptoms, or the
effects of anaemia. These result in chronic ill health and often extensive
medical investigation without a definite diagnosis.
Because coeliac disease can be very effectively treated with a gluten-free diet
it is important to identify people with the undiagnosed disease so as to provide
satisfactory individual treatment and also to improve the overall health of the
community.
To improve the recognition of coeliac disease and to increase the number of
people diagnosed with the condition, the Department of Health asked NICE to
produce a short clinical guideline about how the disease should be recognised
and which people should be assessed for the disease.
The Guideline Development Group (GDG) comprised experts in both adult
and paediatric gastroenterology from primary and secondary care, dietitians,
patient members and a clinical immunologist. It was supported by the NICE
Short Clinical Guidelines Technical Team.
The GDG considered systematically identified and reviewed evidence
concerning the recognition of coeliac disease. A new health economic model
was also developed to consider the cost effectiveness of serological tests for
coeliac disease.
The guideline gives recommendations about the clinical signs, symptoms and
types of presentation or conditions that should alert practitioners to consider
the presence of coeliac disease, and suggests a scheme of investigation to
follow when making the diagnosis. It is expected that implementation of the
guideline recommendations will lead to many new cases being diagnosed and
much ill health being alleviated.
The GDG hopes that this guideline will be sufficiently clear and noncontentious that its implementation will be routine both in secondary care and
in primary care, where most patients with coeliac disease will present.
Professor Peter D Howdle
Chair, Guideline Development Group
Patient-centred care
This guideline offers best practice advice on the recognition and assessment
of coeliac disease and the care of children and adults who are undergoing the
diagnostic process for coeliac disease.
This diagnostic process should take into account patients needs and
preferences. People with symptoms and/or signs suggestive of coeliac
disease should have the opportunity to make informed decisions, in
partnership with their healthcare professionals. If patients do not have the
capacity to make decisions, healthcare professionals should follow the
Department of Health (2001) guidelines Reference guide to consent for
examination or treatment (available from www.dh.gov.uk). Healthcare
professionals should also follow a code of practice accompanying the Mental
Capacity Act (summary available from www.publicguardian.gov.uk).
If the patient is under 16, healthcare professionals should follow guidelines in
Seeking consent: working with children (available from www.dh.gov.uk).
Good communication between healthcare professionals and patients is
essential. It should be supported by evidence-based written information
tailored to the patients needs. Diagnosis, treatment and care, and the
information patients are given about it, should be culturally appropriate. It
should also be accessible to people with additional needs such as physical,
sensory or learning disabilities, and to people who do not speak or read
English.
If the patient agrees, families and carers should have the opportunity to be
involved in decisions about diagnosis, treatment and care.
Families and carers should also be given the information and support they
need.
Care of young people in transition between paediatric and adult services
should be planned and managed according to the best practice guidance
described in Transition: getting it right for young people (available from

www.dh.gov.uk).
Adult and paediatric healthcare teams should work jointly to provide
assessment and services to young people with coeliac disease. Diagnosis
and management should be reviewed throughout the transition process, and
there should be clarity about who is the lead clinician to ensure continuity of
care.
Summary
1.1
Recommendations
When to offer testing

Offer serological testing for coeliac disease to children and adults with any
of the following signs and symptoms:
chronic or intermittent diarrhoea
failure to thrive or faltering growth (in children)
persistent or unexplained gastrointestinal symptoms including
nausea and vomiting
prolonged fatigue (tired all the time)
recurrent abdominal pain, cramping or distension
sudden or unexpected weight loss
unexplained iron-deficiency anaemia, or other unspecified
anaemia.
Offer serological testing for coeliac disease to children and adults with:
any of the following conditions:
autoimmune thyroid disease
dermatitis herpetiformis
irritable bowel syndrome
type 1 diabetes
or
first-degree relatives (parents, siblings or children) with coeliac
disease.
Consider offering serological testing for coeliac disease to children and

adults with any of the following:
Addison's disease
amenorrhoea
aphthous stomatitis (mouth ulcers)
autoimmune liver conditions
autoimmune myocarditis
chronic thrombocytopenia purpura
dental enamel defects
depression or bipolar disorder
Downs syndrome
epilepsy
low-trauma fracture
lymphoma
metabolic bone disease (such as rickets or osteomalacia)
microscopic colitis
persistent or unexplained constipation
persistently raised liver enzymes with unknown cause
polyneuropathy
recurrent miscarriage
reduced bone mineral density
sarcoidosis
Sjgren's syndrome
Turner syndrome
unexplained alopecia
unexplained subfertility.
10
Dietary considerations before testing for coeliac disease

Do not use serological testing for coeliac disease in infants before gluten
has been introduced to the diet.
Inform people (and their parents or carers, as appropriate) that any testing
for coeliac disease is accurate only if the person continues to follow a
gluten-containing diet during the diagnostic process (serological tests and
biopsy if required).
Inform people that they should not start a gluten-free diet until diagnosis is
confirmed by intestinal biopsy, even if a self-test or other serological test is
positive.
Inform people that when they are following a normal diet (containing gluten)
they should eat some gluten (for example, bread, chapattis, pasta, biscuits,
or cakes) in more than one meal every day for a minimum of 6 weeks
before testing; however, it is not possible to say exactly how much gluten
they should eat.
If a person is reluctant or unable to reintroduce gluten into their diet before
testing:
refer them to a gastrointestinal specialist and
inform them that it may be difficult to confirm a diagnosis of
coeliac disease on intestinal biopsy, and that this may have
implications for the prescribing of gluten-free foods.
Other information before serological testing
Inform people who are considering, or have undertaken, self-testing for
coeliac disease (and their parents or carers) that any result from selftesting needs to be discussed with a healthcare professional and confirmed
by laboratory-based tests.
Before seeking consent to take blood for serological tests, explain:
what coeliac disease is
11
that serological tests do not diagnose coeliac disease, but

indicate whether further testing is needed
the implications of a positive test (including referral for intestinal
biopsy and implications for other family members)
the implications of a negative test (that coeliac disease is unlikely
but it could be present or could arise in the future).
Inform people and their parents or carers that a delayed diagnosis of
coeliac disease, or undiagnosed coeliac disease, can result in:
continuing ill health
long-term complications, including osteoporosis and increased
fracture risk, unfavourable pregnancy outcomes and a modest
increased risk of intestinal malignancy
growth failure, delayed puberty and dental problems (in children).
Serological tests
All tests should be undertaken in laboratories with clinical pathology
accreditation (CPA).
Do not use immunoglobulin G (IgG) or immunoglobulin A (IgA) anti-gliadin
antibody (AGA) tests in the diagnosis of coeliac disease.
Do not use of self-tests and/or point-of-care tests for coeliac disease as a
substitute for laboratory-based testing.
When clinicians request serology, laboratories should:
use IgA tissue transglutaminase (tTGA) as the first choice test
use IgA endomysial antibodies (EMA) testing if the result of the
tTGA test is equivocal
check for IgA deficiency if the serology is negative1
1 Investigation for IgA deficiency should be done if the laboratory detects a

low or very low optical density on IgA tTGA test or low background on IgA
EMA test.
12
use IgG tTGA and/or IgG EMA serological tests for people with
confirmed IgA deficiency
communicate the results clearly in terms of values, interpretation
and recommended action.
Do not use human leukocyte antigen (HLA) DQ2/DQ8 testing in the initial
diagnosis of coeliac disease. (However, its high negative predictive value
may be of use to gastrointestinal specialists in specific clinical situations.)
After serological testing
Offer referral to a gastrointestinal specialist for intestinal biopsy to confirm
or exclude coeliac disease to people with positive serological results from
any tTGA or EMA test.
If serology tests are negative but coeliac disease is still clinically suspected,
offer referral to a gastrointestinal specialist for further assessment.
13
Recognition an assessment
1.2
Care pathway
Important: Do not use serological testing for coeliac disease in infants before gluten has been introduced to the diet
Does the person have any of the signs, symptoms

or conditions listed in box A or box B?
No
Person is unlikely to need

testing for coeliac disease at
this point, unless there is a
continuing medical problem
or clinical suspicion
Yes
Is the person on a glutencontaining diet?
No
Yes
Offer serological testing if the person has any of the

signs, symptoms or conditions in box A
Consider offering serological testing if the person
has any of the conditions in box B
Is the person willing/able to

reintroduce gluten to their diet?
No
Refer them to a
gastrointestinal
specialist and inform
them that it may be
difficult to confirm a
diagnosis of coeliac
disease on intestinal
biopsy, and that this may
have implications for
their ability to access
prescribed gluten-free
foods
Information needs
Dietary considerations before serological testing
Other information before serological testing
Inform people (and their parents or carers as appropriate)

that:
Inform people who are considering, or who have undertaken, self-testing for
testing (serology and biopsy if required) is accurate

only if they follow a gluten-containing diet
coeliac disease that any result from self-testing needs to be discussed with a
healthcare professional and confirmed by laboratory-based tests.
when following a gluten-containing diet they should eat

some gluten in more than one meal every day for at
least 6 weeks before testing

that serological tests do not diagnose coeliac disease, but indicate whether
further testing is needed
they should not start a gluten-free diet until diagnosis is

confirmed by intestinal biopsy (even if a self-test or
other serological test is positive)
the implications of a positive test (including referral for intestinal biopsy and
implications for other family members)
the implications of a negative test (that coeliac disease is unlikely but it

could be present or arise in the future).
Inform people (and their parents or carers as appropriate) that a delayed

diagnosis of coeliac disease, or undiagnosed coeliac disease, can result in:

long-term complications, including osteoporosis and increased fracture risk,
unfavourable pregnancy outcomes and a modest increased risk of intestinal
malignancy
Serology testing and after
Important:
All tests should be undertaken in laboratories with clinical pathology accreditation (CPA)
Do not use IgA or IgG anti-gliadin antibody (AGA) tests in the diagnosis of coeliac disease
Do not use HLA DQ2/DQ8 testing in the initial diagnosis of coeliac disease (However, its high negative
predictive value may be of use to gastrointestinal specialists in specific clinical situations)
Do not use self-tests and/or point of care tests for coeliac disease as a substitute for laboratory-based
testing
Use serological testing for IgA tissue

transglutaminase (tTGA) as a first-choice test
Use IgA endomysial antibodies (EMA) testing if
the result of the tTGA test is equivocal
Check for IgA

deficiencya
Negative
result
Positive
result
Offer IgG tTGA tests

and/or IgG EMA tests
Positive result
Negative result
but continuing
clinical suspicion
Negative
result, no
further reason
to suspect
coeliac
disease
Unlikely to have coeliac

disease
No need to repeat tests
Refer to a gastrointestinal
specialist for intestinal biopsy to
confirm or exclude coeliac
disease
Negative result
but continuing
clinical suspicion
Positive result
Investigation for IgA deficiency should be done if the laboratory

detects a low or very low optical density on IgA tTGA test or low
background on IgA EMA test.
Signs, symptoms and conditions associated with coeliac disease

a
Box A. Offer serological testing to children and adults with any

of the following signs, symptoms and conditions
Signs and symptoms
c
Conditions
Chronic or intermittent diarrhoea
Autoimmune thyroid disease
Failure to thrive or faltering growth (in
Dermatitis herpetiformis
children)
Irritable bowel syndrome
Persistent or unexplained gastrointestinal
Type 1 diabetes
symptoms including nausea and vomiting
First-degree relatives (parents, siblings or
Prolonged fatigue (tired all the time)
Recurrent abdominal pain, cramping or
children) with coeliac disease
distension
Sudden or unexpected weight loss
Unexplained iron-deficiency anaemia, or

other unspecified anaemia
Box B. Consider offering serological testing to children and

adults with any of the following
Addison's disease
microscopic colitis
amenorrhoea
persistent or unexplained
constipation
persistently raised liver enzymes with
unknown cause
polyneuropathy
Downs syndrome
sarcoidosis
epilepsy
Sjgren's syndrome
low-trauma fracture
Turner syndrome
lymphoma
metabolic bone disease (such as

rickets or osteomalacia)
1.3
Overview
1.1.1
Coeliac disease: recognition and assessment
Coeliac disease is a state of heightened immunological response to ingested

gluten in genetically susceptible people. Gluten is a protein that is present in
wheat, barley and rye. Historically, coeliac disease was believed to be
uncommon; however, population-based studies have identified that it is more
common than previously thought.
Coeliac disease has traditionally been associated with mainly gastrointestinal
symptoms (such as diarrhoea, abdominal pain, bloating, constipation and
indigestion), because chronic inflammation of the small intestine is a feature
of the immune response to gluten. However, non-gastrointestinal features of
coeliac disease have been increasingly recognised in people presenting with
the disease. Some people with coeliac disease have no obvious symptoms.
Coeliac disease is considered to be more prevalent in people with
autoimmune conditions such as type 1 diabetes or autoimmune thyroid
disease, and in first-degree relatives of people with coeliac disease.
Coeliac disease can be diagnosed at any age (after the introduction of glutencontaining foods to the infant weaning diet), and presents in both children and
adults.
Because of the disparate nature of its signs and symptoms, and the historical
belief that it is not a common disease, there is concern that coeliac disease
often goes unrecognised and consequently is underdiagnosed. As a result,
people may present to primary and secondary care on many occasions and
with a range of symptoms before diagnosis. Delayed diagnosis is a concern
because the symptoms of coeliac disease remain untreated and because of
the possible long-term effects of undiagnosed coeliac disease.
There is also some uncertainty about which of the serological tests are most
suitable for use in the diagnostic process for coeliac disease. Small intestinal
biopsy is used as the reference standard for the diagnosis of coeliac disease.
Nice clinical guideline 86 Coeliac disease
18
Although there is ongoing debate about the possibility of diagnosis without the
need for an intestinal biopsy, it is accepted that currently it is needed for a
definitive diagnosis.
This short clinical guideline aims to improve the care of children and adults
with undiagnosed coeliac disease by making evidence-based
recommendations about its recognition, and about using serological testing to
direct referral for definitive diagnosis by intestinal biopsy.
This guideline uses the best available clinical-effectiveness and costeffectiveness evidence, which is analysed and discussed by the GDG to
develop recommendations. The GDG considered the signs and symptoms,
conditions likely to coexist with coeliac disease, the role of serological testing
in the diagnostic process up to referral for small intestinal biopsy, and the
information needs of patients and carers throughout this process.
1.3.1
The NICE short clinical guideline programme
Coeliac disease: recognition and assessment' (NICE clinical guideline 86) is a

NICE short clinical guideline. For a full explanation of the NICE guideline
development process, see The guidelines manual (2009) (available from
www.nice.org.uk/guidelinesmanualwww.nice.org.uk).
1.3.2
Using this guideline
This document is intended to be relevant to healthcare professionals in

primary and secondary care. The target population is adults and children with
symptoms and/or signs that suggest coeliac disease.
This is the full version of the guideline. It is available from
www.nice.org.uk/CG86. Printed summary versions of this guideline are
available: Understanding NICE guidance (a version for patients and carers)
and a quick reference guide (for healthcare professionals). These are also
available from www.nice.org.uk/CG86.
19
1.3.3
Using recommendations and supporting evidence
For each clinical question the GDG was presented with a summary of the
clinical evidence, and economic evidence if appropriate, derived from the
studies reviewed and appraised. The GDG based the guideline
recommendations on this information. The link between the evidence and the
view of the GDG in making each recommendation is made explicit in the
'Evidence to recommendations' sections (2.2.3, 2.3.4 and 2.4.5).
Evidence review
2.1
Introduction
The clinical-effectiveness and cost-effectiveness evidence that was used in

the development of this guideline is summarised in this section. Further
details about the cost-effectiveness evidence, including details of the
economic model, are given in appendix 6.5; details about the clinical evidence
are given in the tables in appendix 6.6.
The aim of this guideline is to improve the recognition and assessment of
coeliac disease in children and adults; it considers the diagnostic pathway up
to referral for intestinal biopsy. Small intestinal biopsy is the reference
standard used throughout this guideline; the studies included are those in
which coeliac disease was confirmed by intestinal biopsy. In 2004 the Agency
for Healthcare Research and Quality (AHRQ) published an evidence
report/technology assessment on coeliac disease. The report included a
series of systematic reviews using clearly defined methods; these reviews
have been included when appropriate to the scope of this guideline. The
AHRQ report, assessed as a well-conducted systematic review, is considered
as high-quality evidence (details of the evidence grading system can be found
in The guidelines manual [2009], available from www.nice.org.uk). Other
studies included in this guideline have been mainly cohort-based studies,
notably for the evidence of serological test accuracy. Casecontrol studies
have also been included when appropriate. Both the cohort and casecontrol
studies have limitations resulting from study design, and as such are regarded
as level + evidence. Case series, case reports and studies with small
20
numbers (less than 50 participants) have not been included. When both signs
and symptoms and coexisting conditions have been listed in this guideline
they have been listed alphabetically.
2.2
Prevalence of coeliac disease
2.2.1
Evidence review
The prevalence of coeliac disease has historically been difficult to determine

because in many cases people with coeliac disease do not have specific
signs and symptoms. Difficulties in recognising coeliac disease have resulted
in its prevalence being considerably underestimated.
A search was carried out to identify large population-based studies giving data
on the prevalence of coeliac disease; these are reviewed below.
Overall prevalence of coeliac disease
The AHRQ report (2004) includes studies that considered the prevalence of
coeliac disease in north America and western Europe up to and including
2003. The evidence below includes the AHRQ report with additional relevant
large population-based studies in north America and western Europe from
2003 onwards and studies in other geographical areas from 1990. The AHRQ
report found a prevalence of coeliac disease in children by biopsy of 0.5 to
1.6% (six studies) and by serology of 0.3 to 1.9% (eight studies); in adults the
prevalence by biopsy was 0.07 to1.9% (15 studies) and by serology was 0.2
to 2.7% (22 studies). The three UK-based studies in the AHRQ report are all
of adults, and identify a prevalence of coeliac disease by biopsy of 1.0% and
by serology of 0.8 to 1.9%.
The Avon Longitudinal Study of Parents and Children (a population-based
cohort study) used IgA EMA to investigate children aged 7.5 years and
reported that 1% (54 out of 5470) were serologically positive for coeliac
disease. This study also showed that IgA EMA positive rates were higher in
girls than in boys, odds ratio (OR) 2.12 (95% confidence interval [CI] 1.20 to
3.75) (Bingley et al. 2004).
21
Additional international studies in adults used data which was available from
large samples such as people donating blood (Bdioui et al. 2006; Melo et al.
2006; Oliveria et al. 2007; Pereira et al. 2006; Shahbazkha et al. 2003) and
people attending for prenuptial medical checks (Gomez et al. 2001). A further
study used random sampling from a national register (Roka et al. 2007).
These studies found a prevalence of coeliac disease in adults of 0.14 to
0.86%.
Additional international studies in children used data on children younger than
3 years (Castano et al. 2004), samples from an existing public health register
(Korponay-Szabo et al. 1999) and random sampling of school children (Ben
Hariz et al. 2007; Ertekin et al. 2005). These studies identified a prevalence of
coeliac disease in children of 0.64 to 1.17%.
The AHRQ report (2004) also included studies on the prevalence of coeliac
disease in both children and adults in whom coeliac disease was suspected.
These studies were mainly situated in referral centres and the prevalence of
coeliac disease varied widely: in children it was 1.1 to 4.0% with EMA
serology, 4.6 to 17.0% with biopsy; in adults it was 1.5% with EMA serology,
11.6 to 50.0% with biopsy.
Prevalence in first-degree relatives
The AHRQ report (2004) included studies that considered the prevalence of
coeliac disease in first-degree relatives of people who had had a diagnosis of
coeliac disease. These studies showed a prevalence of 2.8 to 17.2% with
serology (five studies) and 5.6 to 44.1% with biopsy (12 studies). The three
studies completed in the UK all reported a prevalence found using biopsy, and
reported a prevalence in first-degree relatives of 5.6 to 22.5%.
Three additional studies were included (Fraser et al. 2006; Biagi et al. 2008;
Szaflaraka-Sczepanik et al. 2001). These reported a prevalence of coeliac
disease in first-degree relatives of 2 to 17.7%. The study by Fraser et al. was
in the UK and reported a prevalence of 5.5%.
22
2.2.2
I.
Evidence statements
In national studies in the UK, the prevalence of coeliac disease
ranges between 0.8% and 1.9%. This is broadly similar to other
international studies.
II.
Among first-degree relatives of people with coeliac disease, the

majority of studies report a prevalence of coeliac disease between
4.5% and 12%.
III.
There is limited evidence that the prevalence of coeliac disease is

twice as high in females as in males.
2.3
The possible long-term consequences of

undiagnosed coeliac disease
2.3.1
Evidence review
The review considered only the possible long-term consequences of

undiagnosed coeliac disease, and therefore did not include any studies that
considered people with diagnosed coeliac disease. It did not include
consideration of any long-term consequences of coeliac disease that may
affect coexisting conditions such as type 1 diabetes. The included studies
looked at undiagnosed coeliac disease or where other possible long-term
consequences had been noted as present at the point of diagnosis. It should
be noted that these possible long-term consequences are associations and
the studies are not considered to provide evidence of a causal relationship. In
all but one of the included studies coeliac disease had been confirmed by
biopsy; the other study included pregnant women and intestinal biopsy was
not considered ethical in those near to delivery (Greco et al. 2004). Overall
evidence was identified in three areas: pregnancy outcomes, fracture risk and
malignancy.
Pregnancy outcomes
An Italian study of 5055 women admitted to obstetric and gynaecological
wards (Greco et al. 2004) identified no pregnancy outcomes for which there
was a significant difference between women with and without coeliac disease.
23
Outcomes included risk of spontaneous abortion, premature delivery, low birth

weight and intrauterine growth retardation (IUGR).
A Swedish study analysed data on people from a national inpatient register
who had a hospital-based discharge record of coeliac disease (Ludvigsson et
al. 2005). It included 929 women whose coeliac disease had not been
diagnosed when they gave birth, and 2,822,805 women without coeliac
disease. There were significant differences between outcomes in the two
groups of women. IUGR was reported in 5.5% of mothers with undiagnosed
coeliac disease, and in 3.1% of mothers without coeliac disease (adjusted
odds ratio [OR] 1.62, 95% confidence interval [CI] 1.22 to 2.15, p = 0.001).
The equivalent figures for low-birth-weight were 7.0% and 3.4% (adjusted OR
2.13, 95% CI 1.66 to 2.75, p < 0.001); for very-low-birth-weight 1.2% and
0.5% (adjusted OR 2.45, 95% CI 1.35 to 4.43, p = 0.003); for preterm birth
8.0% and 5.0% (adjusted OR 1.71, 95% CI 1.35 to 2.17, p < 0.001); and for
caesarean section 3.4% and 2.3% (adjusted OR 1.82, 95% CI 1.27 to 2.60,
p = 0.001). No significant difference was found between the groups for very
preterm birth (before 30 weeks) or for babies with low Apgar scores (less
than 7).
Fracture risk
A second Swedish study using the national inpatient register (Ludvigsson et
al. 2007) considered hip fractures (14,187 in patients with coeliac disease;
68,852 in patients without coeliac disease) and any fractures (13,724 in
patients with coeliac disease; 65,627 in patients without coeliac disease). The
estimated association of coeliac disease and prior fractures showed an
increased risk of diagnosis with coeliac disease after hip fracture (OR 2.0,
95% CI 1.6 to 2.5, p < 0.001) and after any fracture (OR 1.6, 95% CI 1.5 to
1.8, p < 0.001). This study also identified significantly higher rates of hip
fractures in people with undiagnosed coeliac disease compared with those
with diagnosed coeliac disease. This increased risk was seen throughout the
time period from 10 years to 0.01 years before diagnosis of coeliac disease.
A Danish study used the national patient discharge register to consider
fracture risk in people with coeliac disease (Vestergaard et al. 2002). This
24
study identified no increase in fracture risk before diagnosis of coeliac disease

compared with matched controls for skull and jaw fractures, spine, rib and
pelvis fractures, upper arm fractures, forearm fractures, Colles fractures,
hand and finger fractures, hip and femur fractures, fractured neck of femur,
lower leg fractures, foot fractures and osteoporosis.
Malignancy
A US study considered the standardised mortality ratio (SMR) of observed to
expected rates for cancers that were diagnosed before or simultaneously with
coeliac disease diagnosis (Green et al. 2003). Although numbers were small,
this study identified significant SMRs for non-Hodgkins lymphoma (4
observed cases compared with 0.7 expected, SMR 5.3, 95% CI 2.3 to 13,
p < 0.001), small bowel cancer (3 vs. 0.1, SMR 45, 95% CI 34 to 61,
p < 0.001), oesophageal cancer (3 vs. 0.2, SMR 16, 95% CI 9.7 to 26,
p < 0.001) and melanoma (4 vs. 0.8, SMR 5, 95% CI 2.1 to 12, p < 0.001). It
did not identify a significant difference SMR for colon cancer, breast cancer
and total cancers.
An Italian study considered the impact of delayed diagnosis of coeliac disease
on cancer risk using a standardised incidence ratio (SIR) of observed
compared with expected cases in 1968 adults with diagnosed coeliac disease
(Silano et al. 2007). In this study 55 people were diagnosed with cancer
before or simultaneously with coeliac disease diagnosis, compared with
42.1 expected cases (SIR 1.3, 95% CI 1.0 to 1.7). Although numbers involved
were small, this study identified 20 observed cases compared with
4.2 expected of non-Hodgkin's lymphoma (SIR 4.7, 95% CI 2.9 to 7.3), for
colon cancer 7 compared with 6.2 (SIR 1.1, 95%CI 0.68 to 1.56), for small
bowel cancer 5 compared with 0.19 (SIR 25, 95% CI 8.5 to 51.4) and for
Hodgkins lymphoma 4 compared with 0.4 (SIR 10, 95% CI 2.7 to 25). A lower
risk was identified for breast cancer in people with newly diagnosed coeliac
disease (3 vs. 14, SIR 0.2, 95% CI 0.04 to 0.62).
2.3.2
IV.
Evidence statements
There is evidence that undiagnosed maternal coeliac disease has
a negative effect on intrauterine growth and birth weight, and is
25
associated with increased preterm birth and caesarean section

rates.
V.
Evidence suggests an association between undiagnosed coeliac

disease and an increased risk of fractures.
VI.
Undiagnosed coeliac disease is associated with an increased risk

of non-Hodgkins and Hodgkins lymphoma and small bowel
cancer, but overall rates are low.
2.3.3
Linking evidence to recommendations
The GDG discussed the evidence, agreed the evidence statements relating to
the possible effects of long-term undiagnosed coeliac disease, and developed
recommendations. This discussion is summarised here:
The GDG agreed the need to include information about the risk of longterm complications of undiagnosed coeliac disease. It noted that although
there is an increased risk of the specific cancers with undiagnosed coeliac
disease, the overall risk of developing these cancers is low.
The GDG discussed the different possible long-term effects in children and
adults and agreed an additional recommendation for children specifying
growth failure, delayed puberty and dental complications.
2.4
Signs and symptoms of coeliac disease and

coexisting conditions with coeliac disease
2.4.1
Evidence review signs and symptoms
Recognition and assessment of coeliac disease can be difficult because of the

variety of presenting signs and symptoms.
The AHRQ report considered the prevalence of coeliac disease in adults with
iron-deficiency anaemia and in adults with low bone-mineral density. Eight
studies from the AHRQ report with 50 or more participants were included;
these were all in adults with biopsy-proven coeliac disease. The prevalence of
coeliac disease in people with iron-deficiency anaemia ranged from 2.3 to
15%. Four studies from the AHRQ report considered people with low bone
26
mineral density; these studies identified a prevalence of coeliac disease

ranging from 0 to 3%.
Further papers included in this review considered people with coeliac disease
at the point of it being diagnosed and the features that they presented with.
(Those reported in table 1 are where 5% or more of participants had the
presenting feature.)
Table 1 Presenting features of people with coeliac disease
a)
Feature
b)
P
eo
pl
e
wi
th
th
e
fe
at
ur
e
c)
Adults/chil
dren
d)
Studies
e)
Irondeficiency
anaemia
f)
39
.3
%
i)
adults and
children
l)
Bottaro
1999
g)
j)
k)
adults
m)
25
%
Brandi
marte
2002
h)
11
.7
%
n)
Emami
2008
p)
16
%
t)
adults and
children
x)
Dickey
1997
q)
3
to
19
%
u)
v)
w)
children
y)
Garamp
azzi
2007
z)
Ramper
tab
2006
aa)
Vilppula
2008
o)
Other or
unspecifie
d anaemia
r)
ab)
Anorexia
adults and
children
adults
older adults
3.
0
to
12
.7
%
s)
23
.3
%
ac)
7.
8
%
ae)
adults and
children
ag)
Bottaro
1999
af)
children
ah)
Bottaro
27
a)
ai)
av)
bf)
Feature
Weight
loss
Abdominal
distension/
bloating
Abdominal
pain
b)
P
eo
pl
e
wi
th
th
e
fe
at
ur
e
ad)
25
.6
to
35
.1
%
aj)
43
.6
to
59
.6
%
ak)
6
%
al)
15
.6
%
am)
16
.7
%
aw)
28
.4
to
35
.8
%
c)
Adults/chil
dren
d)
Studies
1993
an)
ao)
ap)
aq)
az)
ba)
bb)
children
ar)
adults and
children
Bottaro
1993
as)
Dickey
1997
at)
Hopper
2008
au)
Vilppula
2008
children
bc)
adults and
children
Bottaro
1993
bd)
Emami
2008
be)
Garamp
azzi
2007
adults
older adults
children
ax)
10
%
ay)
20
to
39
%
bg)
12
%
bj)
adults and
children
bm)
Dickey
1997
bh)
8.
2
%
bk)
adults and
children
bn)
Emami
2008
bl)
children
bo)
Garamp
azzi
bi)
11
to
28
a)
Feature
b)
P
eo
pl
e
wi
th
th
e
fe
at
ur
e
21
%
c)
Adults/chil
dren
d)
Studies
2007
bp)
Abdominal
pain/disten
sion/flatule
nce
bq)
31
.7
%
br)
older adults
bs)
Vilppula
2008
bt)
Vomiting
bu)
26
.1
to
32
.5
%
bv)
children
bw)
Bottaro
1993
bx)
Flatulence
by)
5.
4
%
bz)
adults and
children
ca)
Emami
2008
cb)
Diarrhoea
cc)
70
.2
to
75
.2
%
cj)
ck)
children
cq)
adults and
children
Bottaro
1993
cr)
adults and
children
Dickey
1997
cs)
Emami
2008
ct)
Garamp
azzi
2007
cu)
Hopper
2008
cv)
Ramper
tab
2006
cw)
Vippula
2008
cd)
51
%
ce)
13
.1
%
cf)
12
to
60
%
cg)
42
.9
%
ch)
37
.2
to
91
.3
%
cl)
cm)
cn)
co)
cp)
29
children
adults
adults
older adults
a)
cx)
Feature
Short
stature/gro
wth failure
b)
P
eo
pl
e
wi
th
th
e
fe
at
ur
e
ci)
25
%
cy)
19
.2
%
cz)
20
.2
to
30
.8
%
c)
Adults/chil
dren
d)
Studies
da)
adults and
children
dc)
Bottaro
1999
db)
children
dd)
Bottaro
1993
de)
Irritability
df)
10
.3
to
13
.9
%
dg)
children
dh)
Bottaro
1993
di)
Alopecia
dj)
10
%
dk)
adults
dl)
Brandi
marte
2002
dm)
Osteoporo
sis
dn)
6
%
do)
adults
dp)
Brandi
marte
2002
dq)
Recurrent
aphthous
stomatitis
dr)
6
%
ds)
adults
dt)
Brandi
marte
2002
du)
Amenorrho
ea/
recurrent
abortion
dv)
6
%
dw)
adults
dx)
Brandi
marte
2002
dy)
Hypertrans
aminaseaemia
dz)
6
%
ea)
adults
eb)
Brandi
marte
2002
ec)
Abnormal
liver
biochemist
ry
ed)
5
%
ee)
adults and
children
ef)
Dickey
1997
eg)
Chronic
eh)
ej)
adults and
el)
Dickey
30
a)
Feature
b)
P
eo
pl
e
wi
th
th
e
fe
at
ur
e
%
c)
ei)
8.
3
%
ek)
older adults
em)
Vilppula
2008
fatigue
Adults/chil
dren
d)
children
Studies
1997
en)
Failure to
thrive
eo)
48
to
89
%
ep)
children
eq)
Garamp
azzi
2007
er)
Constipati
on
es)
4
to
12
%
et)
children
eu)
Garamp
azzi
2007
ev)
Irregular
bowel
habits
ew)
4
to
12
%
ex)
children
ey)
Garamp
azzi
2007
Three further studies considered a specific symptom or presentation and the

percentage of those presenting with it who also had coeliac disease:
Karnam et al. (2004) considered adults who were undergoing endoscopy
for iron-deficiency anaemia and found 3 of 105 people (2.9%) had coeliac
disease.
Imanzadeh et al. (2005) considered children with small bowel type chronic
diarrhoea and found that 54 of 825 people (8.96%) had coeliac disease.
Sanders et al. (2005) considered adults with acute abdominal pain and
found that 9 of 300 people (3%) had coeliac disease. In people with nonspecific abdominal pain 10.5% had coeliac disease.
31
Some people presenting with the features of coeliac disease in the studies
summarised in table 1 had a coexisting condition at the point of diagnosis of
coeliac disease:
dermatitis herpetiformis 10%, Brandimarte 2002 (adults); 1%, Dickey
1997 (adults and children)
irritable bowel syndrome 20.2%, Emami 2008 (adults and children)
liver disorder 0.85%, Emami 2008 (adults and children)
rheumatological disorder 0.28%, Emami 2008 (adults and children)
Crohns disease 0.57%, Emami 2008 (adults and children)
bone disease 0 to15%, Rampertab 2006 (adults)
malignancy 5 to 21.7%, Rampertab 2006 (adults).
2.4.2
Evidence review coexisting conditions
The studies included for this review considered coexisting conditions

associated with coeliac disease up to and including the point of it being
diagnosed. Studies that considered subsequent development of conditions in
people who had been diagnosed with coeliac disease were excluded. The
relationship between the coexisting conditions and coeliac disease here is not
considered to be causal; the aim was to examine whether people with certain
conditions have a higher rate of coeliac disease than the general population.
Papers in which there was a substantial discrepancy between numbers of
people who had serological tests and numbers of people who had biopsies
were excluded, because of the possibility that results could be biased if not all
those with positive serology had a biopsy.
Type 1 diabetes
The AHRQ report included papers on the prevalence of coeliac disease in
people with type 1 diabetes; 21 of these studies (people with coeliac disease
proven by biopsy; each had 50 or more participants) were included here.
These studies identified a prevalence of coeliac disease in people with type 1
diabetes of 1.4 to 8.2% in children, 0.3 to 11.3% in adults and 1.7 to 5.7% in
combined child and adult studies. Two additional papers also considered
people with type 1 diabetes: one in children reported that 6.6% had coeliac
32
disease (Salardi et al. 2008) and one in adults reported that 6.4% had coeliac
disease (Picarelli et al. 2005).
Other conditions
Papers were included that considered cohorts of people with specified other
conditions who were tested for coeliac disease (see table 2).
33
Table 2 Coexisting conditions and coeliac disease
34
ez)
C
o
n
di
ti
o
n
fa)
Study
participants
fb)
Participa
nts with
coeliac
disease
fc)
Stud
y
auth
or
and
year
fd)
Ar
th
riti
s
fe)
160 adults with

rheumatoid
arthritis
ff)
0.63%
fg)
Fran
cis
200
2
fi)
62 children with
juvenile chronic
arthritis
fj)
1.5%
fk)
Geo
rge
199
6
fm)
119 children
with juvenile
chronic arthritis
fn)
2.5%
fo)
Lep
ore
199
6
A
ut
oi
m
m
un
e
th
yr
oi
d
fq)
136 adults with

autoimmune
thyroiditis
fr)
2.9%
fs)
Gulit
er
200
7
fu)
152 adults with

autoimmune
thyroid disease
fv)
3.29%
fw)
Sate
gnaGuid
etti
199
8
fx)
D
o
w
n
fz)
1453 children
and adults
ga)
gb)
Gold
acre
200
4
fy)
sy
nd
ro
m
e
4 (0.3%),
adjusted
risk ratio
4.7 (95%
CI 1.3 to
12.2)
gd)
1110 children,
92 adults
ge)
55 (4.6%)
gf)
Bon
amic
o
200
1
gh)
255 children
and adults
gi)
2 (0.8%)
gj)
Prat
esi
200
3
gl)
177 adults
gm)
1:44
(2.3%)
gn)
Cron
in
199
8
gp)
354 adults (173

Crohns
gq)
0.85%
gr)
Lee
ds
fp)
gg)
go)
E
pil
ep
sy
Inf
la
35
ez)
C
o
n
di
ti
o
n
m
m
at
or
y
bo
w
el
di
se
as
e
fa)
fb)
gs)
Irr
ita
bl
e
bo
w
el
sy
nd
ro
m
e
gt)
300 adults
gu)
OR 7
(95% CI
1.7 to
28.0)
gv)
San
ders
200
1
gw)
Li
ve
r
di
se
as
e
gx)
624 adults with

chronic
hepatitis C
gy)
0%
gz)
Thev
enot
200
7
hb)
738 children
and adults with
chronic liver
disease
hc)
1:185
(0.45%)
hd)
Ger
meni
s
200
5
hf)
57 adults with
primary biliary
cirrhosis
hg)
7%
hh)
Dick
ey
199
7
Study
participants
Participa
nts with
coeliac
disease
fc)
disease, 154
ulcerative
colitis, 27 other
conditions)
36
Stud
y
auth
or
and
year
200
7
ez)
C
o
n
di
ti
o
n
fa)
Study
participants
fb)
Participa
nts with
coeliac
disease
fc)
Stud
y
auth
or
and
year
hi)
Ly
m
ph
oi
d
m
ali
gn
an
cy
hj)
298 adults
hk)
0.67%
hl)
Farr
e
200
4
hm)
M
yo
ca
rdi
tis
hn)
187 adults with

autoimmune
myocarditis
ho)
4.4% (p <
0.003 vs.
control
group)
hp)
Frus
taci
200
2
37
ez)
C
o
n
di
ti
o
n
fa)
Study
participants
fb)
Participa
nts with
coeliac
disease
fc)
Stud
y
auth
or
and
year
hq)
Sj
g
re
n'
s
sy
nd
ro
m
e
hr)
111 adults
hs)
4.54%
ht)
Szo
dora
y
200
4
hu)
S
ub
fe
rtil
ity
hv)
99 women
hw)
3.03%
(p = 0.037
unexplain
ed
infertility
vs. control
group)
hx)
Melo
ni
199
9
hz)
150 women
ia)
2.7% all
unexplain
ed
infertility
(p = 0.06
vs. control
group)
ib)
Colli
n
199
6
389 children
and adults
ie)
25 (6.4%)
if)
Bon
amic
o
200
2
ic)
Tu id)
rn
er
sy
nd
ro
m
e
One study was also included that identified the existing conditions of people at
the point of diagnosis of coeliac disease (Collin et al. 1994). Also included
were studies in which logistical regression had been used to investigate
coeliac disease that developed following a prior history of a coexisting
condition (see table 3).
38
Table 3 Coexisting conditions and coeliac disease

ig)
Study
group:
people
with
newly
diagno
sed
coeliac
diseas
e
ih)
ii)
335
adults
(335
control
group)
(figures
are
given
for
study
group
first,
control
group
second)
ik)
ij)
Coexisting conditions
il)
Connective tissue disorder: 7.2% vs. 2.7%, p = 0.011
Sjgren's syndrome 11 (3.3%) vs. 1 (0.3%), p = 0.0059
rheumatoid arthritis 6 (1.8%) vs. 7 (2.1%)
im)
Pulmonary disorders:
asthma 9 vs. 12
sarcoidosis 5 vs. 0
in)
(Collin
1994)
Endocrine disorders: 12% (study group) vs. 4.2%

(control group), p = 0.0003
insulin dependent diabetes 18 (5.4%) vs. 5 (1.5%),
p = 0.0094
autoimmune thyroid 18 (5.4%) vs. 9 (2.7%)
Neurological disorders:
epileptic seizures 5 vs. 3
dementia 5 vs. 1
io)
iq)
Liver diseases: 4 vs. 0
ip)
14,349
adults
and
children
(69,998
control)
(Ludvig
sson
2007a)
ir)
14,371
adults
and
children
(70,096
control)
(Ludvig
sson
2007b)
is)
Increased risk of coeliac disease in those with prior

polyneuropathy OR 5.4, 95% CI 3.6 to 8.2, p < 0.001
it)
Other neurological diseases were not associated with

subsequent coeliac disease
13,776
adults
and
children
iv)
Increased risk of coeliac disease in those with history

of mood disorder:
prior depression OR 2.3, 95% CI 2.0 to 2.8, p < 0.001
iu)

sarcoidosis OR 3.58, 95% CI 1.98 to 6.45, p < 0.001
39
ig)
iw)
Study
group:
people
with
newly
diagno
sed
coeliac
diseas
e
(66,815
control)
(Ludvig
sson
2007c)
ih)
13,818
adults
and
children
(66,584
control)
(Ludvig
sson
2007d)
ix)
prior bipolar disorder OR 1.7, 95% CI 1.2 to 2.3, p = 0.001

of liver disorder:
acute hepatitis OR 4.98, 95% CI 1.59 to 12.06, p = 0.004
chronic hepatitis OR 5.79, 95% CI 3.13 to 10.70,

p < 0.001
primary sclerosing cholangitis OR 4.42, 95% CI 2.38 to
8.24, p < 0.001
fatty liver OR 5.83, 95% CI 1.96 to 17.36, p < 0.002
ascites OR 5.00, 95% CI 2.08 to 12.01, p < 0.001
liver failure, extended OR 5.88, 95% CI 4.05 to 8.54,

p < 0.001
liver failure, restricted OR 8.33, 95% CI 1.99 to 34.87,
p < 0.004
liver cirrhosis/fibrosis OR 5.83, 95% CI 3.86 to 8.81,
p < 0.001
primary biliary cirrhosis OR 15.00, 95 %CI 4.84 to 46.51,
p < 0.001
hepatomegaly OR 2.00 (95% CI 0.39 to 10.31) not
significant
iy)
jc)
14,335
children
and
adults
(69,888
control)
(Ludvig
sson
2007e)
iz)

tuberculosis:
ja)
jb)
OR 2.5, 95% CI 1.75 to 3.55, p < 0.001
15,533
children
and
adults
(14,491
inpatien
jd)

sepsis
je)
jf)
OR 2.2, 95% CI 1.7 to 3.0, p < 0.001
40
ig)
Study
group:
people
with
newly
diagno
sed
coeliac
diseas
e
t
referen
ce
controls
)
(Ludvig
sson
2008)
ih)
jg)
14,366
children
and
adults
(70,095
control)
ji)

Addison's disease OR 8.6, 95% CI 3.4 to 21.8
jj)
jh)
(Elfstr
m
2007)
jk)
14,347
adults
and
children
(69,967
control)
(Olen
2008)
2.4.3
Evidence statements
jl)

of thrombocytopenia purpura OR 2.96, 95% CI 1.60
to 5.50, p = 0.001; and those with prior chronic
thrombocytopenia purpura OR 6.00, 95% CI 1.83 to
19.66, p = 0.003
In children and adults, coeliac disease can present with a broad range of
signs and symptoms. The most frequent are:
abdominal pain, cramping or distension
failure to thrive or faltering growth in children
fatigue
iron-deficiency anaemia
nausea or vomiting
41
weight loss.
The following findings may also be present when coeliac disease is
diagnosed:
abnormal liver biochemistry
alopecia
amenorrhoea
constipation
epilepsy
microscopic colitis
osteoporosis
recurrent abortion
type 1 diabetes.
There is good evidence that coeliac disease has an increased prevalence in
people with:
autoimmune thyroid disease (up to 7%)
irritable bowel syndrome (up to 7%)
type 1 diabetes (210%).
There is some evidence that coeliac disease has an increased prevalence in
people with:
chronic thrombocytopenic purpura
depression/bipolar disorder
Downs syndrome
epilepsy
liver conditions
42
lymphoid malignancy
polyneuropathy
Sjgren's syndrome
sarcoidosis
Turner syndrome
2.4.4
The GDG discussed the evidence and agreed the evidence statements
relating to the signs and symptoms of coeliac disease and the coexisting
conditions, and developed recommendations. This discussion is summarised
here:
The GDG agreed that there were certain signs and symptoms and
coexisting conditions (as well as the known risk factor of being a firstdegree relative of a person with coeliac disease) that are sufficiently
associated with coeliac disease that people with them should be offered
serological testing, and developed recommendations to reflect this. The
GDG discussed the historic division of symptoms into gastrointestinal and
non-gastrointestinal and concluded that it would be more beneficial to
identify the overall signs and symptoms for which testing would be
recommended. The GDG further discussed the non-specific nature of many
of the signs and symptoms and consequently added 'unexplained' and
'chronic' to the description of some signs and symptoms to ensure that
people who may have coeliac disease are identified.
The GDG agreed a list of further signs, symptoms and coexisting
conditions for which they wanted to raise awareness of the link with coeliac
disease. Therefore recommendations were developed that identified where
offering serological testing for coeliac disease should be considered.
The GDG discussed weight loss as a feature of coeliac disease and noted
that, although weight loss can be a symptom of coeliac disease, the
traditional view of a patient with coeliac disease being underweight is no
43
longer true and that patients may present underweight, at a normal weight
or overweight.
Recommendation 1.1.1
Offer serological testing for coeliac disease to children and adults with any of
the following signs and symptoms:
failure to thrive or faltering growth (in children)
persistent or unexplained gastrointestinal symptoms including nausea and
vomiting
prolonged fatigue (tired all the time)
recurrent abdominal pain, cramping or distension
sudden or unexpected weight loss
unexplained iron-deficiency anaemia, or other unspecified anaemia.
Offer serological testing for coeliac disease to children and adults with:
any of the following conditions:
autoimmune thyroid disease
irritable bowel syndrome
type 1 diabetes
or
first-degree relatives (parents, siblings or children) with coeliac disease.
44
Consider offering serological testing for coeliac disease to children and adults
with any of the following:
Addison's disease
amenorrhoea
Downs syndrome
epilepsy
low-trauma fracture
lymphoma
metabolic bone disease (such as rickets or osteomalacia)
microscopic colitis
persistent or unexplained constipation
persistently raised liver enzymes with unknown cause
polyneuropathy
sarcoidosis
Sjgren's syndrome
Turner syndrome
45
Do not use serological testing for coeliac disease in infants before gluten has
been introduced to the diet.
2.5
Serological tests in the diagnostic process for

coeliac disease
2.5.1
Evidence review information for patients before testing
The search strategy was designed to identify any studies that relate
specifically to the information needs and support of patients and parents or
carers before the diagnosis of coeliac disease. No studies were identified.
2.5.2
Evidence review serological tests
This review incorporated studies that included a blood sample drawn from
children or adults suspected of having coeliac disease. This suspicion may
have been based on clinical symptoms, an existing condition (such as type 1
diabetes) or having a first-degree relative with coeliac disease. The included
studies were mainly cohort studies, which provided the best quality evidence.
The data were synthesised and are presented in the form of forest plots and
receiver operating characteristic (ROC) curves (see appendix 6.3). Summary
statistics have not been included because the studies were not considered
homogenous, the methodology for the meta-analysis of diagnostic studies is
not clear and expert opinion in this area varies. Within the studies different kits
and different cut-off values were used for the analysis 2. Further differences
between studies were different or incompletely reported biopsy strategies,
possible variability between laboratories or operators, the use of different
samples or studies taking place in several different countries.
The serological tests considered for this review were:
IgA AGA
IgG AGA
IgA EMA
2 If studies used different cut-off levels, the data used were that of the
manufacturers recommended cut-off levels.
46
IgG EMA
IgA tTGA
IgG tTGA.
Table 4 summarises the studies, total participants, test methods (enzymelinked immunosorbent assay [ELISA] or diffusion in gel [DIG]) and substrate
used for EMA (human umbilical cord [HU] or monkey oesophagus [ME]) and
for tTGA (human recombinant [HR] or guinea pig [GP]) in the included studies.
47
Table 4 Summary of serological test studies
48
jm)
jq)
ju)
S
e
r
o
l
o
g
i
c
a
l
t
e
s
t
jn)
I
g
A
A
G
A
jr)
I
g
G
A
G
A
jv)
jo)
T jp)
o
t
a
l
p
a
r
t
i
c
i
p
a
n
t
s
Methods
js)
5 jt)
6
0
0
24 used ELISA, 5 used DIGELISA, 1 used

immunohistochemistry, 1
used immunofluorescence
jw)
4 jx)
8
2
0
20 used ELISA, 3 used DIGELISA, 1 used

immunohistochemistry, 1
used immunofluorescence
Number of
31
25
jy)
I
jz)
g 21
A
E
M
A
M
E
ka)
5 kb)
2
6
5
18 used
immunofluorescence, 2 used
ELISA, 1 used DIG-ELISA, 1
unknown
kc)
I
kd)
g 3
A
E
M
A
H
U
ke)
2 kf)
6
4
3 used immunofluorescence
kg)
I
kh)
g 1
G
E
M
A
ki)
8 kj)
9
1 used immunofluorescence
49
M
E
kk)
ko)
ks)
kw)
I
g
A
t
T
G
A
G
P
kl)
I
g
A
t
T
G
A
H
R
kp)
I
g
G
t
T
G
A
G
P
kt)
I
g
G
t
T
G
A
H
R
kx)
km)
9 kn)
4
6
8 used ELISA
kq)
3 kr)
8
5
3
9 used ELISA, 1 used

radiobinding assay, 1
unknown
ku)
1 kv)
1
1
1 used ELISA
ky)
2 kz)
5
4
1 unknown
11
IgA deficiency
People with IgA deficiency will have a false negative result if IgA-based
serological tests are used in the diagnosis of coeliac disease. It has been
suggested that there has been inadequate evaluation of IgA deficiency while
testing for coeliac disease, which has resulted in the underdiagnosis of both
(McGowan et al. 2008). Therefore, this guideline also considered the use of
IgA-deficiency testing and IgG-based serological testing in the diagnostic
process for coeliac disease.
50
Included studies
All studies considered people with suspected coeliac disease who had one of
the included serological tests and had coeliac disease confirmed by biopsy.
There were 29 studies included from the AHRQ (2004) report, 18 in children
(Altuntas et al. 1998; Artan et al. 1998; Ascher et al. 1996; Bahia et al. 2001;
Bode et al. 1993; Chan et al. 2001; Chartrand et al. 1997; Chirdo et al. 1999;
Iltanen et al. 1999; Kumar et al. 1989; Lindberg et al. 1985; Lindquist et al.
1994; Maki et al. 1991; Meini et al. 1996; Poddar et al. 2002; Rich et al. 1990;
Russo et al. 1999; Wolters et al. 2002), seven in adults (Bardela et al. 2001;
Bode et al. 1994; Carroccio et al. 2002; Kaukinen et al. 2000; McMillan et al.
1991; Valdimarss et al. 1996; Vogelsang et al. 1995) and four in children and
adults (Carroccio et al. 2002; Gonczi et al. 1991; Tesei et al. 2003; Troncone
et al. 1999). A further 14 studies were identified from the search, four in
children (Del Rosario et al. 1998; Liu et al. 2003 and 2005; Viola et al. 2004),
six in adults (Abrams et al. 2006; Hopper et al. 2008; Johnston et al. 2003;
Kocna et al. 2002; Niveloni et al. 2007; Reeves et al. 2006) and four in
children and adults (Carroccio et al. 2006; Dickey et al. 1997; Emami et al.
2008; Rostami et al. 1999). The largest of the additional studies was based in
the UK and included a cohort of 2000 adults, 77 of whom were diagnosed with
coeliac disease, and included data on IgA/IgG AGA, IgA tTGA and IgA EMA
with biopsy (Hopper et al. 2008).
51
Table 5 Sensitivity/specificity of serological tests for coeliac disease
52
la)
Se
rol
og
ica
l
te
st
lb)
Studies
lc)
Sensiti
vity
ld)
Specifici
ty
le)
Ig
A
A
G
A
lf)
31 studies
(5600
participant
s)
lj)
Range
23
to100%
lm)
Range 45
to100%
ln)
(adults
46 to
100%)
(adults 45
to 100%)
lo)
(childre
n 23 to
100%)
(children
51 to
99%)
lp)
lq)
md)
mq)
mw)
Ig
G
A
G
A
Ig
A
E
M
A
lg)
18 child
studies
lh)
10 adult
studies
li)
3
child/adult
studies
lr)
25 studies
(4830
participant
s)
ls)
15 child
studies
lt)
8 adult
studies
lu)
2
child/adult
studies
me)
23 studies
(5529
participant
s)
lk)
ll)
lv)
Range
46 to
100%
lw)
(adults
22 to
100%)
(childre
n 71 to
100%)
mc)
lx)
Range 77
to 99%
ma)
(adults 41
to 97%)
mb)
(children
38 to
99%)
ly)
mi)
Range
68 to
100%
mj)
(adults
68 to
100%)
(childre
n 46 to
100%)
mp)
mf)
10 child
studies
mg)
9 adult
studies
mh)
4
child/adult
studies
Ig
G
E
M
A
mr)
1 adult
study (89
participant
s)
ms)
Ig
A
tT
G
A
mx)
19 studies
(4799
participant
s)
nb)
Range
38 to
100%
nc)
(adults
lz)
mk)
mm)
Range 89
to 100%
mn)
(adults 94
to 100%)
mo)
(children
77 to
100%)
ml)
Sensitiv
ity 39%
mt)
53
mu)
Specificit
y 98%
mv)
ne)
Range 25
to 100%
nf)
(adults 65
to 100%)
ni)
Ig
G
tT
G
A
my)
6 child
studies
mz)
9 adult
studies
na)
4
child/adult
studies
nj)
2 studies
(365
participant
s)
nk)
1 adult
study
nl)
1
child/adult
study
71 to
100%)
nd)
nm)
(childre
n 89 to
100%)
Sensitiv
ity 23
to 85%
ng)
(children
25 to
100%)
nh)
nn)
Specificit
y 89 to
98%
no)
The overall efficacy of the IgA AGA, IgA EMA and IgA tTGA serological tests
was summarised in forest plots and ROC curves (see appendix 6.3). The
ROC curves below show the overall results for the IgA AGA, tTGA and EMA
tests. They show a lower level of accuracy for the IgA AGA than the other
tests, with both IgA EMA and IgA tTGA identified as having high levels of both
sensitivity and specificity. For AGA the IgA serological tests results appeared
to show higher sensitivity and specificity than the IgG tests. For IgG tTGA and
IgG EMA there were insufficient data available to draw reasonable
conclusions.
54
i0
t.9vy
S
e
n
s
1
.0
0
8
.0
7
.0
6
.0
5
.0
4
.0
3
.0
2
.1
0
1L
0
.
9
0
.
8
0
.
7
0
.
6
0
.
5
0
.
4
0
.
3
0
.
2
0
.
1
0
S
p
e
c
i
f
t
y
e
g
n
d
Ig
A
G
A
E
M
tT
Figure 1 IgA overall results for anti-gliadin antibodies, anti-endomysial
antibodies and anti tissue transglutaminase antibodies
Combined and sequence tests
A small number of papers considered the sensitivity and specificity of test
combinations or sequencing of tests. One large UK study in adults (Hopper et
al. 2008) considered the use of IgA tTGA and EMA. This study identified
improvements in positive predictive value (PPV) and some small differences
in sensitivity, specificity and negative predictive value (NPV) if both tests were
used, either in a two-step process or simultaneously, compared with if tests
were completed individually.
A second UK-based paper (Johnston et al. 2003), also in adults, considered
the results if either IgA tTGA or EMA were positive. Positive results for either
test gave a lower PPV than was found with each test individually, and a higher
NPV than IgA tTGA.
A paper from the Czech Republic (Kocna et al. 2002) considered a two-step
screening algorithm and identified IgA/IgG AGA to be the least accurate
55
first-step marker if it is followed by biopsy, with IgA EMA the most accurate
first-step marker if it is followed by IgA tTGA.
Three studies in the AHRQ report considered the use of IgA/IgG AGA together
or each individually; they did not find the combination results to be notably
different from the individual tests.
Human leukocyte antigen tests
Coeliac disease has a genetic association with certain types of type II human
leukocyte antigens (HLA); HLA DQ2 is found in 95% of people with coeliac
disease and HLA DQ8 in most of the remaining 5%. No studies identified by
the searches considered the sensitivity and specificity of the HLA DQ2 and
DQ8 tests in coeliac disease. The AHRQ report identified papers that
considered the prevalence of HLA DQ2 and DQ8 in a population of people
with coeliac disease, but these studies were not designed to determine the
diagnostic utility of HLA DQ2 or DQ8. Three studies in the AHRQ report were
completed in people with biopsy-proven coeliac disease; these had sensitivity
results of 87 to 90% and specificity of 70 to 81%.
Age
ROC curve analysis categorising studies into those with child participants,
those with adult participants and those with mixed (child and adult)
participants reflected the overall analysis, with both IgA EMA and IgA tTGA
(there is insufficient evidence for IgG in either test to plot on the curves)
showing considerably higher levels of sensitivity and specificity than IgA or
IgG AGA.
One study (Viola 2004) also considered IgA AGA, IgA EMA and IgA tTGA
results in children 2 years and younger and those older than 2 years. It found
similar results in both age categories for IgA tTGA and for IgA EMA.
56
Subgroups
The search for this question was designed to identify studies in which there
was evidence that the serological tests for coeliac disease performed in any
way differently from the general population. The only areas in which studies
were identified were liver disease and IgA deficiency.
Liver disease: one study of 105 participants who had primary biliary
cirrhosis reported a specificity range for IgA tTGA of 82.5 to 97.1% and
95.1 to 100% for IgG tTGA (Bizzaro et al. 2006). The authors noted that
with almost all the antibody concentrations IgA tTGA was close to the cutoff level, and that positive results were inconsistent between the test kits.
They identified a concern about the false-positive rate with IgA tTGA testing
in people with primary biliary cirrhosis, although only six participants had
biopsies.
IgA deficiency: one paper was identified that considered the use of IgG
AGA and IgG tTGA tests in 126 children with IgA deficiency (Lenhardt et al.
2004). Eleven were diagnosed with coeliac disease: all were IgG tTGA
positive and five were also IgG AGA positive, this suggests that IgG tTGA is
more accurate than IgG AGA in children with IgA deficiency.
Newer tests
Deamidated gliadin
Two papers were included that considered the use of deamidated gliadin
peptide (DGP)-based assays as a diagnostic tool for coeliac disease. The first
paper considered the use of IgA and IgG antibodies to synthetic DGP and
tTGA in 176 children (Agardh et al. 2007) and found 119 (68%) with coeliac
disease.
57
Table 6 Sensitivity and specificity results for deamidated gliadin (Agardh

et al. 2007)
np)
nu)
nz)
oe)
oj)
oo)
ot)
Antibody
IgA/G DGP/tTGA
IgA/G DGP
IgA DGP
IgG DGP
IgA tTGA
IgG tTGA
nq)
nv)
oa)
of)
ok)
op)
ou)
S nr)
e
n
s
i
t
i
v
i
t
y
S ns)
p PPV
e
c
i
f
i
c
i
t
y
nt)
1 nw)
0
0
%
9 nx)
4 97.5%
.
7
%
ny)
9 ob)
7
.
5
%
9 oc)
8 99.1%
.
2
%
od)
9 og)
0
.
8
%
9 oh)
4 97.3%
.
7
%
oi)
9 ol)
5
.
0
%
9 om)
8 99.1%
.
2
%
on)
9 oq)
6
.
6
%
1 or)
0 100%
0
%
os)
1 ov)
2
.
6
%
1 ow)
0 100%
0
%
ox)
NPV
100%
94.9%
83.1%
90.3%
93.4%
35.4%
The second study considered 141 adults and used IgA tTGA and IgA/IgG
DGP; 60 were diagnosed with coeliac disease (Niveloni et al. 2007).
58
Table 7 Sensitivity and specificity results for deamidated gliadin

(Niveloni et al. 2007)
oy)
pd)
pi)
pn)
ps)
px)
qc)
qh)
Antibody
IgA DGP
IgG DGP
IgA + IgG DGP
IgA tTGA
IgA DGP + tTGA
oz)
pe)
pj)
po)
pt)
py)
IgG DPG + IgA

tTGA
qd)
IgA+IgG DGP +
tTGA
qi)
59
S pa)
e
n
s
i
t
i
v
i
t
y
S pb)
p PPV
e
c
i
f
i
c
i
t
y
pc)
9 pf)
8
.
3
%
9 pg)
3 92.2%
.
8
%
ph)
9 pk)
6
.
7
%
1 pl)
0 100%
0
%
pm)
9 pp)
8
.
3
%
9 pq)
8 98.3%
.
8
%
pr)
9 pu)
5
.
0
%
9 pv)
7 96.6%
.
5
%
pw)
1 pz)
0
0
%
9 qa)
7 96.7%
.
5
%
qb)
1 qe)
0
0
%
9 qf)
7 96.7%
.
5
%
qg)
1 qj)
0
0
%
9 qk)
6 95.2%
.
3
%
ql)
NPV
98.7%
97.6%
79.6%
96.3%
100%
100%
100%
Results for both of these studies using deamidated gliadin peptide showed
sensitivity and specificity values similar to those found with tTGA.
Immunochromatographic sticks
One paper was included that considered the use of immunochromatographic
sticks3 for tissue transglutaminase and antigliadin antibody screening in 286
children and 49 adults (Ferre-Lopez et al. 2004); 142 (51%) children and 30
(61%) adults were diagnosed with coeliac disease. Sensitivity and specificity
results for immunochromatographic sticks were broadly similar to those from
the ELISA method:
IgA/G tTGA (tTG stick): children sensitivity 97%, specificity 98%; adults
sensitivity 83%, specificity 100%
IgA tTGA (tTG-AGA stick): children sensitivity 96%, specificity 98%; adults
IgA AGA (tTG-AGA stick): children sensitivity 89%, specificity 96%; adults
IgA tTGA + AGA (stick, one test): children sensitivity 99%, specificity 95%;
adults sensitivity 86%, specificity 100%.
2.5.3
Evidence statements
VII. The IgA tTGA and IgA EMA serological tests show high levels of
sensitivity and specificity in the diagnostic process for coeliac
disease.
VIII. Gliadin antibody serological tests show lower levels of sensitivity
and specificity than tTGA and EMA.
IX.
Based on limited clinical evidence, combination testing with IgA

tTGA and IgA EMA does not appear to substantially to improve
accuracy in the diagnostic process.
X.
There is limited evidence that IgA tTGA yields more false positive
results in people with liver disease than in the general population.
3 Can be used for self-test or point of care testing.

60
XI.
Serological tests have comparable accuracy in children and in

adults.
XII. Newer tests for deamidated gliadin may be useful but require
further evaluation.
XIII. Limited evidence suggests that point-of-care tests and self tests
may be accurate but require further evaluation.
XIV. HLA DQ2 or DQ8 is present in approximately 25% of the UK
population so a positive test has no predictive value, but a negative
test can exclude a diagnosis of coeliac disease.
2.5.4
Health economics
Published health economics material

A literature review was conducted to identify evidence on the costeffectiveness of serological tests for coeliac disease.
Several potentially useful studies were identified (Atkinson et al. 1997;
Dretzke et al. 2004; Dorn et al. 2007; Harewood and Murray 2001; Hopper et
al. 2008; Mein and Ladabaum et al. 2004; Shamir et al. 2006; Spiegel et al.
2004; Swigonski et al. 2008; Yagil et al. 2005). The studies by Atkinson et al.
(1997) and Harewood and Murray (2001) were cost-minimisation studies that
compared serological test strategies with biopsy for diagnosing coeliac
disease. Dorn et al. (2007), Hopper et al. (2008) and Yagil et al. (2005) used
cost-effectiveness analysis to examine the costs and diagnostic accuracy of
serological tests for coeliac disease. Dorn et al. (2007) also examined the cost
effectiveness of HLA testing. Mein and Ladabaum (2004) and Spiegel et
al. (2004) examined the cost effectiveness of testing people with irritable
bowel syndrome for coeliac disease. Shamir et al. (2006) examined a
population screening approach in the adult population and Swigonski et al.
(2008) examined the cost effectiveness of screening for coeliac disease in
children with Downs syndrome, with the specific aim of preventing lymphoma.
None of the 10 papers examining the cost effectiveness of serological tests for
coeliac disease was considered directly applicable to this guideline. However,
61
one UK study (Dretzke et al. 2004) examined serological tests and used
quality-adjusted life-years (QALYs) as an outcome measure, so was reviewed
in detail for this guideline. The remaining papers were used to explore
previous approaches to modelling serological test strategies and to inform the
structure of the model but were not quality-assessed or reviewed in detail for
this guideline because they did not include health-related quality-of-life
outcomes and/or were not based in the UK.
A full data extraction form for Dretzke et al. (2004) is available in appendix 6.5
and the techniques from that study (2004) have been examined alongside
careful consideration of the modelling methods used by the other studies
identified in the review.
Summary of Dretzke et al. (2004)
Dretzke et al. (2004) is a full health technology assessment (HTA) of
autoantibody testing in children with newly diagnosed type 1 diabetes. It
includes an economic model to quantify the costs and benefits of screening
for coeliac disease at the time of diagnosis of diabetes. The assessment took
place because of the variation in practice of screening for autoantibodies
associated with coeliac disease in this population.
Six possible screening strategies were compared:
no screening
biopsy of all children
single autoantibody test confirmed by biopsy in those testing positive
combination of autoantibody tests confirmed by biopsy in those testing
positive
single autoantibody test without confirmatory biopsy
combination of autoantibody tests without confirmatory biopsy.
The authors were clear that not all of these strategies are used in current
clinical practice, although all strategies were included for completeness. The
analysis took an NHS perspective, with costs and outcomes modelled over a
lifetime.
62
The prevalence of undiagnosed coeliac disease in children with diabetes was

estimated from the literature. The effectiveness estimates for the serological
tests were taken from the authors systematic review outlined in the report.
The tests considered were IgA AGA, IgG AGA, IgA EMA, IgA ARA and IgA
tTGA. Other tests were excluded because too few studies were found. The
values used in the model were taken from the summary ROC curves
presented in the clinical section of Dretzke et al. (2004) for each test at the
point at which sensitivity and specificity were equal. This is called the Q point.
For combination tests the authors assumed that the results of the tests were
independent and clearly set out the method of calculating sensitivity and
specificity for combination strategies. Adherence to a gluten-free diet was
included in the model, as was the proportion of patients who would have
received a later diagnosis through normal clinical routes if they had not been
previously picked up by screening. The delay to diagnosis for these patients
was included, with associated costs and utilities for undiagnosed coeliac
disease. The authors assumed that the delay to diagnosis was 5 years in the
base case.
Utility estimates (quality of life weights) and assumptions were informed by
existing literature. Studies on quality of life of treated and untreated coeliac
disease were searched and reviewed. Utilities could not be derived directly
from the studies identified. Estimates of the utility of treated and untreated
coeliac disease, and of the disutility of endoscopy, biopsy and gluten-free diet
were derived from the literature and assumptions.
Costs were estimated for serological tests, endoscopy and biopsy, and glutenfree diet. Personal communication was used to evaluate the costs of the
serological tests; this is likely to be because of the absence of a national tariff
for diagnostic tests (such as the British National Formulary for drug prices).
All strategies were compared with a no-screening strategy. The lowest cost
per QALY gained was for a positive IgA EMA with confirmatory biopsy, with an
incremental cost-effectiveness ratio of 12,250 per QALY gained compared
with no screening. The least cost-effective strategies were those using IgG
AGA tests alone or in combination with other autoantibody tests. The authors
63
reported that the results were sensitive to the disutility of being on a glutenfree diet, the cost of gluten-free diet, the differences in utilities between health
states and the reduction in life expectancy as a result of coeliac disease.
An important limitation of this study is that the authors do not present the
costs and QALYs separately in the results section. This makes it difficult to
determine whether costs or QALYs have the most influence on the
incremental cost-effectiveness ratio. Limitations of the individual input
parameters are discussed throughout the methods section, but the discussion
does not address limitations of the overall model.
De novo economic model
In summary, there is evidence on the cost effectiveness of serological tests for
various patient populations and country settings; however, there is a lack of
evidence for the cost effectiveness of serological tests for the patient
population of direct relevance to this guideline.
Because of the lack of published economic evidence that fully addresses the
cost effectiveness of serological testing in the decision-making context of this
guideline, the GDG requested the development of a de novo model. Any costeffectiveness analysis carried out should also examine the costs and
consequences of the outcomes of diagnosis. Although it is outside the scope
of this guideline to make recommendations on the treatment or management
of coeliac disease, the economic evaluation considers the costs and benefits
of current standard practice after diagnosis of coeliac disease. This allows us
to include the long-term consequences of testing, along with the costs and
consequences of incorrect diagnosis.
A model was developed to estimate the cost effectiveness of serological test
strategies for detecting coeliac disease in patients presenting with signs and
symptoms. The model was built and analysed using TreeAge Pro 2007 Suite
(TreeAge software) and adopted a lifetime horizon. Several test strategies
were examined and compared with a no-test strategy (see table 8). The
structure of the decision tree was agreed with the GDG and was also informed
by previous cost-effectiveness studies. Patients accrued costs and utilities
64
depending on their pathway through the model. At the end of the decision
tree, patients entered a Markov model with states reflecting their eventual
diagnosis (that is, diagnosed as having coeliac disease, no diagnosis of
coeliac disease or undiagnosed coeliac disease) and picked up costs and
utilities linked with these states until death.
Serological tests examined in the model were the IgA tTGA and the IgA EMA
tests. These were analysed alone and in combination. In all cases, tests were
followed by biopsy to confirm positive results. Strategies with separate IgA
deficiency testing were also included. For completeness a no-test strategy
and a biopsy-only strategy were included.
Table 8 List of strategies in the model
qm)
Strate
gy
numb
er
qn)
Description
qo)
qp)
IgA tTGA test, followed by biopsy in the case of a

positive result
qq)
qr)
IgA EMA test, followed by biopsy in the case of a

positive result
qs)
qt)
IgA tTGA then IgA EMA in a two-step strategy,

followed by a biopsy if IgA tTGA was positive then
IgA EMA was positive
qu)
qv)
IgA tTGA and IgA EMA in combination, followed by

a biopsy if both tests were positive
qw)
qx)
IgA tTGA and IgA EMA in combination, followed by

a biopsy if either test was positive
qy)
qz)
IgA tTGA test followed by IgA deficiency test, and

biopsy in the case of a positive result or IgA
deficiency
ra)
rb)
IgA EMA test followed by IgA deficiency test, and

biopsy in the case of a positive result or IgA
deficiency
rc)
re)
rd)
rf)
Biopsy all patients
No test for any patients
The clinical systematic review identified several studies on the sensitivity and
specificity of serological tests for coeliac disease. There was no evidence
synthesis for these studies, for reasons explained in appendix 6.4. Therefore
65
data on sensitivity and specificity were taken from a UK-based, good quality
study (Hopper et al. 2008). This evaluated the sensitivity and specificity of
several serological test strategies in 2000 patients who had been referred for
biopsy. The results of the study were confirmed by biopsy. This study was
considered to provide the best available evidence on diagnostic accuracy to
inform the base-case economic model.
The model takes into account the effect on quality of life of having an
endoscopy and biopsy, having coeliac disease, having undiagnosed coeliac
disease and of being on a gluten-free diet, all based on the literature review of
quality of life evidence. It also takes into account any possible increased
mortality resulting from undiagnosed coeliac disease, taken from a review of
the literature on mortality and coeliac disease. Adherence to a gluten-free diet
was taken into account in the model.
The model included the following costs: serological tests, endoscopy and
biopsy, gluten-free diet and follow-up to the NHS, and delayed diagnosis.
Costs were based on national-level costs from published sources, calculations
and data provided by laboratories. Costs were considered from an NHS and
personal social services (PSS) perspective as stated in the guideline scope.
The cost of serological testing is difficult to estimate because there is no
national tariff available. Cost of serological tests can vary greatly depending
on who orders the tests and how they are carried out. Economies of scale are
also realised when using diagnostic equipment, so the cost may differ
depending on the volume of tests carried out by the laboratory. For the
present analysis, the costs of serological tests have been estimated from data
provided by two laboratories in the UK following communication with a GDG
member. It is important to note that the methods laboratories use when
charging for serological tests means that the cost of two tests or combination
testing is often only marginally more expensive than a single test. This is
because most laboratories charge a fixed fee for coeliac disease testing,
based on an average of all tests for coeliac disease including the cost for
tTGA plus any additional tests needed.
66
Given this potential uncertainty on how laboratories charge, extensive

sensitivity analysis was carried out on this variable.
Full details of the model, including results and sensitivity analysis, are
presented in appendix 6.5.
The model suggests that the no-test strategy is both the least effective
strategy (that is, produces the least number of QALYs) and the least costly
strategy. Although no testing costs are involved, people who have
undiagnosed coeliac disease also have a lower quality of life and increased
costs resulting from undiagnosed coeliac disease.
Moving from no testing to any of the testing strategies examined appears to
be cost effective. Comparing the incremental costs and benefits of the testing
strategies with a common comparator (no testing), the model indicates that
there is very little difference between the strategies in terms of cost
effectiveness or clinical effectiveness. This is because of the similarity in the
diagnostic accuracy of these strategies and in the cost of the tests. These
small differences mean that an incremental analysis of the strategies would
not give meaningful results. The test strategies all have incremental costeffectiveness ratios between 4000 to 5300 per QALY gained compared with
no testing, which is well within acceptable levels of cost-effectiveness
thresholds for approval by NICE.
Because all the testing strategies have similar sensitivity and specificity, the
incremental differences in QALYs between them are very small. However, the
biopsy-only strategy is the most expensive, costing about 380 more than the
next most expensive strategy. Therefore, although a biopsy-only strategy may
be preferable to a no-test strategy those strategies that include serological
tests before confirmatory biopsy for positive results are still more cost effective
than the biopsy-only strategy
Combinations of EMA and tTGA tests had sensitivity and specificity similar to
the individual test strategies. The method of costing the test strategies did not
significantly affect the results. Therefore carrying out any of the test strategies
remains cost effective compared to no testing. Sensitivity analysis was carried
67
out to evaluate the effect of charging separately for these tests at high cost.
Even when additive fees are considered, the cost effectiveness is still similar
between the strategies because the costs of the tests are relatively low
compared with the cost and disutility of undiagnosed coeliac disease.
In sensitivity analysis, results were shown to be affected by the increase in
quality of life for treated coeliac disease compared with untreated coeliac
disease. However, even in the extreme case that the utility of treated and
untreated coeliac disease are equal, serological testing remains cost effective
compared with no testing. This is because there is still a difference between
the utility of having coeliac disease (whether treated or untreated) compared
with the utility of not having coeliac disease.
The model is also sensitive to the cost of delayed diagnosis. A threshold
analysis was carried out on this parameter because of the uncertainty around
the additional resources used by people who have coeliac disease but have
not yet been diagnosed. When the cost is relatively low, testing for coeliac
disease is a cost-effective intervention; as the cost of this parameter
increases, testing becomes even more cost effective and specifically, when
the cost of undiagnosed coeliac disease becomes as high as 260 per person
per year, the testing strategies become cost saving.
One-way sensitivity analysis on the most uncertain parameters in the model
showed that the model seems robust to variations in most of the parameter
inputs.
Probabilistic sensitivity analysis was also carried out. Distributions were added
to the sensitivity and specificity of each of the test strategies, the prevalence
of coeliac disease in the population of interest and the cost of delayed
diagnosis. At a threshold of 20,000 per QALY gained (the lower end of the
threshold considered acceptable by NICE), the probability of the test
strategies being cost effective was 100%. At around 6000 per QALY gained,
the probability of each of the strategies becoming cost effective approached
100%.
68
Full details of the model including results, and all sensitivity analyses, are
presented in appendix 6.5.
2.5.5
The GDG discussed the evidence and agreed the evidence statements
relating to the information needs and use of serological tests in the diagnostic
process for coeliac disease and developed recommendations. This discussion
is summarised here:
The GDG discussed the importance of stressing the need to continue a
gluten-containing diet until coeliac disease is diagnosed or excluded using
intestinal biopsy. The need to provide clear information relating to what
coeliac disease is and the place of serological tests in this process was
also identified and recommendations developed. The GDG noted the
importance of clear information to everyone, but also highlighted the
additional support that may be needed by people who have a coexisting
condition, such as type 1 diabetes.
The GDG debated the lack of evidence about the amount of gluten needed
in the gluten-containing diet to maximise the diagnostic potential of the
serological tests and intestinal biopsy. The GDG agreed that this amount
was not known, so it developed a recommendation that acknowledged the
lack of evidence and used the GDG experience and expertise to give a
guide to the amount of gluten to be eaten.
The GDG also considered that people with suspected coeliac disease who
had already begun to exclude gluten from their diet may be reluctant or
unable to re-commence a gluten-containing diet. The GDG considered that
the support and expertise of a gastrointestinal specialist should be
recommended in these situations.
The GDG discussed the pooled results and studies included in the
serological tests review and agreed that the gliadin-based tests had both
lower sensitivity and lower specificity. It therefore agreed to recommend
that gliadin-based tests are not used.
The GDG considered from the clinical evidence and the economic model
that the serological test of choice is IgA tTGA as a first test, and where the
69
results are equivocal then IgA EMA testing should be used. Both the
individual tests and combination testing are clinically effective and cost
effective compared with no testing. The GDG considered that IgA tTGA
should also be recommended as first choice for ease of use and quality
assurance factors.
The GDG recognised that the deamidated gliadin tests and point-of-care
tests or self tests may be of use in the future, but noted that they cannot be
recommended yet because the evidence for them is limited. The GDG also
discussed the need for a recommendation that advises people who may
have used self tests to discuss the results with healthcare professionals,
and that if coeliac disease is suspected patients should have laboratorybased serological tests.
The GDG discussed the evidence relating to the use of IgA tTGA in people
with liver disease. It agreed that, although the available evidence was
limited, the possibility of false positive results in people with liver disease
may be a concern.
The GDG discussed the use of HLA DQ2 and DQ8 testing and noted that
because DQ2 or DQ8 is present in around one quarter of the UK
population, a positive test for it is of limited value in the diagnosis of coeliac
disease. However, it noted the potential use of a negative result in a
specialist setting where serology and biopsy have proven inconclusive.
The GDG noted the need for all serological testing to be undertaken at an
accredited laboratory, and developed a recommendation to reflect this.
The GDG noted the lack of evidence regarding the possibility of repeat
serological testing for coeliac disease, specifically in people with coexisting
conditions for whom serological testing has been recommended (including
type 1 diabetes and autoimmune thyroid disease). It was felt, with the lack
of evidence and without expert consensus, that a recommendation on
repeat testing could not be made. A research recommendation in this area
was developed.
Inform people (and their parents or carers, as appropriate) that any testing for
coeliac disease is accurate only if the person continues to follow a glutenNice clinical guideline 86 Coeliac disease
70
containing diet during the diagnostic process (serological tests and biopsy if
required).
Inform people that they should not start a gluten-free diet until diagnosis is
confirmed by intestinal biopsy, even if a self-test or other serological test is
positive.
Inform people that when they are following a normal diet (containing gluten)
they should eat some gluten (for example, bread, chapattis, pasta, biscuits, or
cakes) in more than one meal every day for a minimum of 6 weeks before
testing; however, it is not possible to say exactly how much gluten they should
eat.
If a person is reluctant or unable to reintroduce gluten into their diet before
testing:
refer them to a gastrointestinal specialist and
inform them that it may be difficult to confirm a diagnosis of coeliac disease
on intestinal biopsy, and that this may have implications for the prescribing
of gluten-free foods.
Inform people who are considering, or have undertaken, self-testing for
coeliac disease (and their parents or carers) that any result from self-testing
needs to be discussed with a healthcare professional and confirmed by
laboratory-based tests.
71
that serological tests do not diagnose coeliac disease, but indicate whether
further testing is needed
the implications of a positive test (including referral for intestinal biopsy and
implications for other family members)
the implications of a negative test (that coeliac disease is unlikely but it
could be present or could arise in the future).
Inform people and their parents or carers that a delayed diagnosis of coeliac
disease, or undiagnosed coeliac disease, can result in:
long-term complications, including osteoporosis and increased fracture risk,
unfavourable pregnancy outcomes and a modest increased risk of
intestinal malignancy
All tests should be undertaken in laboratories with clinical pathology
accreditation (CPA).
Do not use immunoglobulin G (IgG) or immunoglobulin A (IgA) anti-gliadin
antibody (AGA) tests in the diagnosis of coeliac disease.
Do not use of self-tests and/or point-of-care tests for coeliac disease as a
substitute for laboratory-based testing.
72
When clinicians request serology, laboratories should:
use IgA tissue transglutaminase (tTGA) as the first choice test
use IgA endomysial antibodies (EMA) testing if the result of the tTGA test is
equivocal
check for IgA deficiency if the serology is negative4
use IgG tTGA and/or IgG EMA serological tests for people with confirmed
IgA deficiency
communicate the results clearly in terms of values, interpretation and
recommended action.
Do not use human leukocyte antigen (HLA) DQ2/DQ8 testing in the initial
diagnosis of coeliac disease. (However, its high negative predictive value may
be of use to gastrointestinal specialists in specific clinical situations.)
Offer referral to a gastrointestinal specialist for intestinal biopsy to confirm or
exclude coeliac disease to people with positive serological results from any
tTGA or EMA test.
If serology tests are negative but coeliac disease is still clinically suspected,
offer referral to a gastrointestinal specialist for further assessment.
4 Investigation for IgA deficiency should be done when the laboratory detects
a low optical density (OD) on IgA tTGA test, very low IgA tTGA results or low
background on IgA EMA test.
73
2.6
Research recommendations
Dietary assessment of gluten content of diet before serological testing:

what is the minimum gluten dietary content necessary for the optimal
accuracy of serological tests and intestinal biopsy for the diagnosis of
coeliac disease?
There is no robust evidence on how much gluten people should include
in their diet when undergoing testing for coeliac disease. Different
definitions are used, based on a single study and expert opinion, and
this can lead to confusion among patients and clinicians. Although it is
evident that a gluten-containing diet for a sustained period is necessary
to ensure that serological test results are as accurate as possible and
that intestinal biopsy results are as clear as possible, the amount of
gluten and the period of intake needed are unknown. Research is
needed on how serological tests and intestinal biopsy accuracies are
associated with gluten intake in order to define the minimum level of
gluten and period of intake for adults and children with suspected coeliac
disease.
How many people with undiagnosed coeliac disease are misdiagnosed as
having other conditions, and what are the clinical and cost implications of
this?
People with coeliac disease often have significant health problems that
resolve with correct diagnosis and treatment. If coeliac disease is
undiagnosed, or misdiagnosed as another condition, health problems
continue, resulting in the use of inappropriate interventions and
resources, such as visits to GPs or outpatient clinics. Misdiagnosis can
also limit further investigation (and thus correct diagnosis) and the health
problems continue or increase, with a corresponding effect on the
persons quality of life. There are no reliable data on the extent to which
coeliac disease is misdiagnosed in adults and children; high-quality
population-based studies are needed to assess the associated clinical
outcomes and costs in adults and children with undiagnosed coeliac
disease.
74
Should repeat serological testing for coeliac disease be performed, and if

so, how often?
Currently, serological tests (tTGA and EMA) for coeliac disease are both
relatively sensitive and specific, with low rates of false-negative results. It
is not clear whether coeliac disease develops over time (that is, an
individual can be tested for coeliac disease at one point in time and be
true-negative and then tested at a later point in time, and be truepositive). There is a lack of evidence on the need for repeat testing.
Studies are needed to determine whether serological tests should be
repeated if the initial results are negative and there is no high clinical
suspicion of coeliac disease, and if so, when and how often they should
be repeated.
Does adherence to a gluten free diet improve diabetes-related outcomes in
people with coeliac disease and type 1 diabetes?
There is some evidence that glycaemic control is improved in people
with type 1 diabetes who have coeliac disease and follow a gluten-free
diet, but this evidence is not conclusive. Good quality, longitudinal cohort
studies are needed to determine whether adherence to a gluten-free diet
improves diabetes-related outcomes in adults and children with newlydiagnosed type 1 diabetes and coeliac disease. Such outcomes should
include blood glucose control, cardiovascular risk factors (including
weight), diabetic-related complications, and health-related quality of life.
Is the prevalence of coeliac disease higher in adults and children with
autism than in the general population?
There is no conclusive evidence on the prevalence of coeliac disease in
people with autism. Anecdotally, higher rates of coeliac disease are seen
in people with autism, and when diagnosed, adherence to a gluten-free
diet improves both gastrointestinal symptoms and behavioural problems.
Research is needed to determine the prevalence of coeliac disease in
people with autism and whether any behavioural problems improve
following diagnosis.
What are the long-term effects of undiagnosed coeliac disease?
75
Undiagnosed coeliac disease is associated with several long-term

complications, including osteoporosis and some malignancies. Longterm follow-up studies are needed to determine the long-term
complications associated with undiagnosed coeliac disease in adults and
children, and the effect of diagnosis of coeliac disease and adherence to
a gluten-free diet on these complications.
How reliable are serological tests compared with intestinal biopsy in
detecting early coeliac disease?
Evidence of the presence of coeliac disease can be suggested by the
finding of highly specific and sensitive antibodies to tissue
transglutaminase and to endomysium. Confirmation of the presence of
intestinal damage revealed by the histological examination of smallintestinal biopsies remains the traditional method of making the
diagnosis. The sensitivity of this investigation has rarely, if ever, been
formally investigated. With increased use of serological tests for coeliac
disease it has become evident that some people with positive coeliac
autoantibodies have apparently normal small-intestinal histology. Some
such people are, nonetheless, symptomatic and have gluten-sensitive
malabsorption. Early detection of coeliac disease may be important to
prevent long-term complications, Therefore longitudinal studies are
needed to determine whether serological markers are superior and can
reliably detect early coeliac disease before intestinal damage occurs.
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85
3.2
Glossary
2 x 2 table
A table that summarises diagnostic information (true and false positives and
negatives) and allows for further interpretation of the data such as sensitivity,
specificity, forest plots and ROC curves.
Casecontrol study
Comparative observational study in which the investigator selects people who
have experienced an event (for example, developed a disease) and others
who have not (controls), and then collects data to determine previous
exposure to a possible cause.
Cohort study
An observational study in which a defined group of people (the cohort) is
followed over time. Outcomes are compared in subsets of the cohort who
were exposed or not exposed (or exposed at different levels) to an
intervention or other factor of interest.
Confidence interval
The range within which the true' values (for example, size of effect of an
intervention) are expected to lie with a given degree of certainty (for example,
95% or 99%). (Note: confidence intervals represent the probability of random
errors, but not systematic errors or bias).
Cost-effectiveness analysis
An economic evaluation that compares alternative options for a specific
patient group, looking at a single effectiveness dimension measured in a nonmonetary (natural) unit. It expresses the result in the form of an incremental
(or average or marginal) cost-effectiveness ratio.
Costutility analysis
An economic evaluation that compares alternative options for a specific
patient group, looking at a single effectiveness dimension measured in a nonmonetary (natural) unit that also takes quality of life into account. It expresses
the result in the form of incremental cost per quality-adjusted life year (QALY)
gained.
86
Economic evaluation
Technique developed to assess both costs and consequences of alternative
health strategies and to provide a decision-making framework.
False negative
A negative result in a diagnostic test when the person being tested does
possess the attribute for which the test is conducted.
False positive
A positive result in a diagnostic result when the person being tested does not
possess the attribute for which the test is conducted.
Generalisability
The degree to which the results of a study or systematic review can be
extrapolated to other circumstances.
Heterogeneity
A term used to illustrate the variability or differences among studies. High
heterogeneity indicates greater differences.
Negative predictive value
The proportion of people with negative test results who do not have the
disease.
Odds ratio
A measure of treatment effectiveness. The likelihood of an event happening in
the intervention group, divided by the likelihood of it happening in the control
group. The odds ratio is the ratio of non-events to events.
Positive predictive value
The proportion of people with a positive test result who actually have the
disease.
Quality-adjusted life year (QALY)
A statistical measure, representing 1 year of life, with full quality of life.
87
Randomised controlled trial (RCT)

A form of clinical trial to assess the effectiveness of medicines or procedures,
in which participants are randomly assigned to receive a treatment or a
placebo. Considered reliable because it tends not to be biased.
Reference standard
An agreed standard, for example for a test or treatment, against which other
interventions can be compared.
Relative risk
Also known as risk ratio; the ratio of risk in the intervention group to the risk in
the control group. The risk (proportion, probability or rate) is the ratio of people
with an event in a group to the total number of people in the group. A relative
risk (RR) of 1 indicates no difference between the groups being compared.
Sensitivity (of a test)
The proportion of people classified as positive by the reference standard who
are correctly identified by the study test.
Specificity (of a test)
The proportion of people classified as negative by the reference standard who
are correctly identified by the study test.
True negative
A negative result in a diagnostic test, when the person does not possess the
attribute for which the test is conducted.
True positive
A positive result in a diagnostic test, when the person does possess the
attribute for which the test is conducted.
Utility
A measure of the strength of a person's preference for a specific health state
in relation to alternative health states. The utility scale assigns numerical
values on a scale of 0 (death) to 1 (optimal or 'perfect' health). Health states
can be considered worse than death and thus have a negative value.
Estimates of utility ideally based on the use of standardised and validated
88
generic instruments such as EQ-5D are critical in the calculation of healthrelated quality of life weights used in QALYs.
3.3
Abbreviations
rg)
AGA
rh)
Anti-gliadin antibodies
ri)
CI
rj)
Confidence interval
rk)
rm)
ro)
rq)
rs)
ru)
rw)
ry)
sa)
sc)
se)
EMA
rl)
rn)
rp)
rr)
rt)
rv)
rx)
rz)
sb)
sd)
sf)
Anti-endomysial antibodies
Methods
2.1
Aim and scope of the guideline
2.1.1
Scope
IgA
IgG
NPV
OR
PPV
QALY
RCT
RR
SD
tTGA
Immunoglobulin A
Immunoglobulin G
Negative predictive value
Odds ratio
Positive predictive value
Quality-adjusted life year
Randomised controlled trial
Relative risk
Standard deviation
Anti tissue transglutaminase
antibodies
NICE guidelines are developed in accordance with a scope that defines what
the guideline will and will not cover (see appendix 1). The scope of this
guideline is available from www.nice.org.uk/CG86
The aim of this guideline is to provide evidence-based recommendations to
guide healthcare professionals in the recognition and assessment of coeliac
disease in children and adults.
2.2
Development methods
This section sets out in detail the methods used to generate the
recommendations for clinical practice that are presented in the previous
chapters of this guideline. The methods used to develop the
89
recommendations are in accordance with those set out by NICE in The

guidelines manual' (2009; available from www.nice.org.uk).
3.3.1
Developing the guideline scope
The scope for this guideline defined the areas the guideline would and would
not cover. It was prepared by the Short Clinical Guidelines Technical Team in
consultation with relevant literature and following a workshop with clinical
experts and patient groups. The scope was also refined following public
consultation.
2.2.1
Forming and running the Short Clinical Guideline

Development Group
The short clinical guideline on recognition and assessment of coeliac disease

was developed by a Guideline Development Group consisting of 10 members,
including healthcare professional and patient/carer members who were
recruited through open advertisement, and the Short Clinical Guidelines
Technical Team.
2.2.2
Developing key clinical questions
The key clinical questions were refined from the scope and formed the
starting point for the subsequent evidence reviews and facilitated the
development of recommendations by the Guideline Development Group. The
Guideline Development Group and Short Clinical Guidelines Technical Team
agreed appropriate review parameters (inclusion and exclusion criteria) for
each question or topic area. The full list of key clinical questions is given in
appendix 6.2.
2.2.3
Developing recommendations
For each key question, recommendations were derived from the clinical- and
cost-effectiveness evidence reviews and the economic model developed for
this guideline, which were presented to and discussed, alongside their expert
opinion, by the Guideline Development Group.
90
2.2.4
Literature search
The evidence reviews used to develop the guideline recommendations were

underpinned by systematic literature searches, following the methods
described in The guidelines manual' (2009). The purpose of systematically
searching the literature is to attempt to comprehensively identify the published
evidence to answer the key clinical questions developed by the Guideline
Development Group and Short Clinical Guidelines Technical Team.
The search strategies for the key clinical questions were developed by the
Information Services Team with advice from the Short Clinical Guidelines
Technical Team. Structured clinical questions were developed using the PICO
(population, intervention, comparison, outcome) model and were translated
into search strategies using subject heading and free text terms. The
strategies were run across a number of databases with no date restrictions
imposed on the searches.
To identify economic evaluations the NHS Economic Evaluation Database
(NHS EED) and the Health Economic Evaluations Database (HEED) were
searched. Search filters to identify economic evaluations and quality of life
studies were used to interrogate bibliographic databases. There were no date
restrictions imposed on the searches.
In addition to the systematic literature searches, the Guideline Development
Group was asked to alert the Short Clinical Guidelines Technical Team to any
additional evidence, published, unpublished or in press, that met the inclusion
criteria.
The searches were undertaken between May and October 2008. Full details
of the systematic search, including the sources searched and the MEDLINE
strategies for each evidence review, are presented in appendix 6.4.
2.2.5
Reviewing the evidence
The aim of the clinical review was to systematically identify and synthesise
relevant evidence in order to answer the key clinical questions developed
from the guideline scope. The guideline recommendations were evidence
91
based if possible; if evidence was not available, informal consensus within the
Guideline Development Group was used. Future research needs were also
specified in research recommendations.
The papers chosen for inclusion were then critically appraised by the Short
Clinical Guidelines Technical Team for their methodological rigour against a
number of criteria that determine the validity of the results. These criteria
differed according to study type, and the level of evidence ascribed to them
was based on the checklists included in The guidelines manual (2009).
The data were extracted to standard evidence table templates. The findings
were summarised by the Short Clinical Guidelines Technical Team into both a
series of evidence statements and an accompanying narrative summary.
2.2.6
Grading the evidence
Intervention studies
Studies that meet the minimum quality criteria were ascribed a level of
evidence to help the guideline developers and the eventual users of the
guideline understand the type of evidence on which the recommendations
have been based.
NICE uses elements of the GRADE (Grading of Recommendations
Assessment, Development and Evaluation) approach for questions about
interventions in its clinical guidelines. The GRADE working group is
developing an approach for summarising the evidence for diagnostic tests and
strategies. In the absence of this system a narrative summary of the quality of
the evidence is used, based on the quality appraisal criteria from QUADAS
(Quality Assessment of Studies of Diagnostic Accuracy included in Systematic
Reviews). Numerical summaries and analyses are followed by short evidence
statements summarising what the evidence shows (more details can be found
in The guidelines manual [2009]).
2.2.7
Evidence to recommendations
Recommendations were drafted after discussion of the clinical- and costeffectiveness evidence, including consideration of the quality of the available
92
evidence, and using the experience of Guideline Development Group

members. The 'linking evidence to recommendations' sections of the guideline
aim to reflect this decision-making process and provide transparency about
the development of the recommendations. The Guideline Development Group
was able to agree recommendations through informal consensus.
2.2.8
Health economics
An economic evaluation aims to integrate data on the benefits (ideally in

terms of quality-adjusted life years [QALYs]), harms and costs of alternative
options. An economic appraisal will consider not only whether a particular
course of action is clinically effective, but also whether it is cost effective (that
is, value for money). If a particular treatment strategy were found to yield little
health gain relative to the resources used, then it could be advantageous to
redirect resources to other activities that yield greater health gain.
A systematic review of the economic literature relating to the recognition and
assessment of coeliac disease was also conducted.
2.2.9
Consultation
The draft of the full guideline was available on the website for consultation
from 15 January to 12 February 2009, and registered stakeholders were
informed by NICE that the documents were available. Non-registered
stakeholders could view the guideline on the NICE website.
2.2.10
Other national guidance
None relevant.
2.2.11
Piloting, implementation and audit
It is beyond the scope of the work to pilot the contents of this guideline or
validate any approach to implementation. Implementation support tools for
this guideline will be available from the Implementation Team at NICE. The
guideline recommendations have been used to develop clinical audit criteria
for use in practice. Audit criteria are essential implementation tools for
monitoring the uptake and impact of guidelines and thus need to be clear and
straightforward for organisations and professionals to use. NICE develops
93
audit support for all its guidance programmes as part of its implementation
strategy.
2.2.12
Scheduled review of this guideline
Following the 4-week public consultation period the comments made by

stakeholders, peer reviewers and the Guideline Review Panel were collated
and presented anonymously for consideration by the Guideline Development
Group, responses and changes to the guideline were agreed by the Short
Clinical Guidelines Technical Team and the Guideline Development Group to
create the final version of the guideline.
This guideline will be considered for an update following the current process
(chapter 14 of The guidelines manual [2009]).
Contributors
3.1
The Guideline Development Group
The Guideline Development Group is composed of relevant healthcare

professionals, patient representatives and NICE technical staff.
The members of the Guideline Development Group are listed below.
David Wray (Chair of GDG 1)
Professor of Oral Medicine
Peter Howdle (Chair of GDG 3 and 4)
Professor of Clinical Medicine
Adrian Thomas
Consultant Paediatric Gastroenterologist
Alison Lister
Patient/carer member
David Sanders
Consultant Gastroenterologist
94
John O'Malley
General Practitioner
Julian Walters
Consultant Gastroenterologist
Mohamed Abuzakouk
Consultant Immunologist
Norma McGough
Patient/carer member
Peter Macfarlane
Consultant Paediatrician
Sorrel Burden
Dietitian
3.1.1
The Short Clinical Guidelines Technical Team
The Short Clinical Guidelines Technical Team is responsible for this guideline
throughout its development. It is responsible for preparing information for the
Guideline Development Group, for drafting the guideline and for responding to
consultation comments. The following people, who are employees of NICE,
make up the technical team working on this guideline.
Fergus Macbeth (Chair of GDG 2)
Director, Centre for Clinical Practice
Tim Stokes
Associate Director, Centre for Clinical Practice
Beth Shaw
Technical Adviser
Roberta Richey
Technical Analyst
95
Ruth McAllister
Technical Analyst (Health Economics)
Michael Heath
Project Manager
Daniel Tuvey
Information Specialist
Nicole Elliott
Guidelines Commissioning Manager
Emma Banks
Guidelines Coordinator
3.1.2
Guideline Review Panel
Dr John Hyslop Acting Chair

Consultant Radiologist, Royal Cornwall Hospital NHS Trust
Dr Graham Archard
General Practitioner, Dorset
Ms Karen Cowley
Practice Development Nurse, York
Dr David Gillen
Medical Director, Wyeth Pharmaceutical
Ms Catherine Arkley
Lay member
3.1.3
List of stakeholders
Addisons Disease Self-Help Group

Association for Clinical Biochemistry
Association of the British Pharmaceuticals Industry (ABPI)
Barnsley Hospital NHS Foundation Trust
96
Barnsley PCT
Bournemouth and Poole PCT
British Dietetic Association
British Geriatrics Society
British National Formulary (BNF)
British Nuclear Medicine Society
British Society of Gastroenterology
British Society of Gastrointestinal and Abdominal Radiology (BSGAR)
British Society of Paediatric Gastroenterology, Hepatology & Nutrition
(BSPGHAN)
BUPA
Cambridge University Hospitals NHS Foundation Trust (Addenbrookes)
Care Quality Commission (CQC)
Cheshire PCT
Coeliac UK
College of Emergency Medicine
Commission for Social Care Inspection
Connecting for Health
Department for Communities and Local Government
Department of Health
Department of Health, Social Security and Public Safety of Northern Ireland
DHSSPSNI
97
Diabetes UK
Faculty of Public Health
Glutafin
Guys and St Thomas NHS Trust
Harrogate and District NHS Foundation Trust
Imperial College Healthcare NHS Trust
Infant and Dietetic Foods Association
Institute of Biomedical Science
Leeds PCT
Leeds Teaching Hospitals NHS Trust
Luton & Dunstable Hospital NHS Foundation Trust
Manchester Royal Infirmary
Medicines and Healthcare Products Regulatory Agency (MHRA)
Milton Keynes PCT
National Osteoporosis Society
National Patient Safety Agency (NPSA)
National Public Health Service Wales
National Treatment Agency for Substance Misuse
NCCHTA
NHS Bedfordshire
NHS Clinical Knowledge Summaries Service (SCHIN)
98
NHS Direct
NHS Kirklees
NHS Knowsley
NHS Plus
NHS Purchasing & Supply Agency
NHS Quality Improvement Scotland
NHS Sefton
NHS Sheffield
North Yorkshire and York PCT
Nottingham University Hospitals NHS Trust
PERIGON Healthcare Ltd
Primary Care Society for Gastroenterology (PCSG)
Royal College of General Practitioners
Royal College of Nursing
Royal College of Paediatrics and Child Health
Royal College of Pathologists
Royal College of Physicians London
Royal College of Radiologists
Royal Free Hospital NHS Trust
Royal Society of Medicine
SACAR
99
Scottish Intercollegiate Guidelines Network (SIGN)

Sedgefield PCT
Sheffield PCT
Sheffield Teaching Hospitals NHS Foundation Trust
Shire Plc
Shrewsbury & Telford Hospital NHS Trust
Social Care Institute for Excellence (SCIE)
South Asian Health Foundation
South Devon Acute Trust
Teva UK Limited
United Kingdom Clinical Pharmacy Association (UKCPA)
University Hospital Birmingham NHS Foundation Trust
University of Oxford
Wellfoods Ltd
Welsh Assembly Government
Welsh Scientific Advisory Committee (WSAC)
Western Cheshire Primary Care Trust
Western Health and Social Care Trust
York NHS Foundation Trust
100
3.2
Declarations
3.2.1
Authorship and citation
Authorship of this full guideline document is attributed to the NICE Short

Clinical Guidelines Technical Team and members of the Guideline
Development Group under group authorship.
The guideline should be cited as:
National Institute for Health and Clinical Excellence (2009) Coeliac
disease: recognition and assessment of coeliac disease. London:
National Institute for Health and Clinical Excellence. Available from:
www.nice.org.uk/CG86
3.2.2
Declarations of interest
A full list of all declarations of interest made by this Guideline Development

Group is available on the NICE website (www.nice.org.uk).
Please note the appendices are available as separate files.
101

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Issue date: May 2009

NICE clinical guideline 86

NICE clinical guideline 86

The appendices are available as separate files.

Key clinical questions and protocols

ROC curves and forest plots

Health economics evidence and evidence tables

NICE clinical guideline 86 Coeliac disease

NICE clinical guideline 86 Coeliac disease

NICE clinical guideline 86 Coeliac disease

NICE clinical guideline 86 Coeliac disease

NICE clinical guideline 86 Coeliac disease

described in Transition: getting it right for young people (available from

NICE clinical guideline 86 Coeliac disease

When to offer testing

NICE clinical guideline 86 Coeliac disease

Consider offering serological testing for coeliac disease to children and

NICE clinical guideline 86 Coeliac disease

Dietary considerations before testing for coeliac disease

NICE clinical guideline 86 Coeliac disease

that serological tests do not diagnose coeliac disease, but

1 Investigation for IgA deficiency should be done if the laboratory detects a

NICE clinical guideline 86 Coeliac disease

Does the person have any of the signs, symptoms

Person is unlikely to need

Is the person on a glutencontaining diet?

Offer serological testing if the person has any of the

Is the person willing/able to

Dietary considerations before serological testing

Other information before serological testing

Inform people (and their parents or carers as appropriate)

testing (serology and biopsy if required) is accurate

Before seeking consent to take blood for serological tests, explain:

when following a gluten-containing diet they should eat

what coeliac disease is

they should not start a gluten-free diet until diagnosis is

the implications of a negative test (that coeliac disease is unlikely but it

Inform people (and their parents or carers as appropriate) that a delayed

continuing ill health

growth failure, delayed puberty and dental problems (in children).

Serology testing and after

Use serological testing for IgA tissue

Check for IgA

Offer IgG tTGA tests

Unlikely to have coeliac

Investigation for IgA deficiency should be done if the laboratory

Signs, symptoms and conditions associated with coeliac disease

Box A. Offer serological testing to children and adults with any

Chronic or intermittent diarrhoea

Autoimmune thyroid disease

Failure to thrive or faltering growth (in

Irritable bowel syndrome

Persistent or unexplained gastrointestinal

symptoms including nausea and vomiting

First-degree relatives (parents, siblings or

Prolonged fatigue (tired all the time)

Recurrent abdominal pain, cramping or

children) with coeliac disease

Sudden or unexpected weight loss