1

Screening for Coeliac Disease

A Narrative Review

Daniel Stray, Medical Student

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo

Project Thesis - MED5090

February 2021

2

ABSTRACT

Introduction: Many people live with undiagnosed coeliac disease. This could potentially have

a negative impact on their health and well-being. Detecting coeliac disease is possible through

serological testing for autoantibodies against transglutaminase 2. However, while Norway has

screening programmes in place for other diseases, there is no such programme for coeliac

disease. Instead, case finding is based on the individual clinician suspecting coeliac disease,

which yields sub-optimal results. In an effort to study potential improvement in diagnostic

rates, this review looks at the possibility of screening for coeliac disease in Norway.

Methods: To best cover the relevant literature in this narrative review, a non-systematic

literature search was done incorporating medical, economical, ethical and practical

considerations regarding coeliac disease screening in Norway. This included research articles,

government policies reports and international guidelines on coeliac disease.

Results: Studies of coeliac disease screening have generally yielded very good results in at-

risk groups like close relatives of index patients and individuals with other autoimmune

disorders. Mass screening of the general population has also shown relatively good results

depending on the population. Although there is some uncertainty with regards to the natural

course of disease in screening detected coeliac disease patients, and thus the value of

treatment, screening is generally appreciated by the diagnosed individuals. Additionally,

international guidelines generally support at-risk screening for coeliac disease.

Conclusion: Initiating at-risk screening in groups such as close relatives and type 1 diabetes

patients seems the right choice from a public health perspective. Furthermore, given the

promising results of mass screening in other comparable countries, at least testing it out in a

Norwegian setting appear to be justifiable.

3

SAMMENDRAG

Introduksjon: Mange mennesker lever med udiagnostisert cøliaki. Dette kan potensielt ha

negative konsekvenser for deres helse og velvære. Å oppdage cøliaki er mulig ved serologisk

testing for autoantistoffer mot transglutaminase 2. Likevel, på tross av at Norge har

screeningprogrammer på plass for andre sykdommer, finnes ikke noe slikt for cøliaki. I stedet

er diagnostisering avhengig av at den enkelte kliniker mistenker cøliaki, noe som gir

suboptimale resultater. For bedre å forstå hvordan diagnostisering av cøliaki kan forbedres tar

denne oversikten for seg muligheten for cøliakiscreening i Norge.

Metoder: For best å dekke relevant litteratur i denne samfunnsorienterte oversikten, ble et

ikke-systematisk litteratursøk gjort for å finne medisinske, økonomiske, etiske og praktiske

avveininger når det gjelder cøliakiscreening i Norge. Dette inkluderte forskningsartikler,

rapporter og lover fra offentlige myndigheter og internasjonale retningslinjer knyttet til

cøliaki.

Resultater: Studier av cøliakiscreening har generelt gitt veldig gode resultater i risikogrupper

som nære slektninger av indekspasienter og individer med andre autoimmune sykdommer.

Massescreening av hele befolkningen har også gitt relativt gode resultater avhengig av

hvilken befolkning som har blitt studert. Riktignok er det usikkerhet knyttet til det naturlige

forløpet av sykdommen blant screeningoppdagede cøliakipasienter, noe som gjør verdien av

behandling noe mer usikker. Likevel er screening generelt godt tatt imot blant

screeningdiagnostiserte individer. Videre er det generelt støtte blant internasjonale

retningslinjer for screening i risikogrupper.

Konklusjon: Oppstart av screening i risikogrupper slik som nære slektninger og individer med

type 1 diabetes fremstår som det riktige fra et folkehelseperspektiv. Videre, gitt de lovende

resultatene fra massescreening i sammenlignbare land, virker i det minste testing av et slikt

program også i Norge rettferdiggjort.

4

FOREWORD

This thesis was written with the supervision of my main supervisor Professor Ludvig M.

Sollid, University of Oslo, and co-supervisor Jorunn Stamnæs, University of Oslo. A few

years back in 2018 Ludvig Sollid invited me to join his research group focused on coeliac

disease as a medical reaserch programme student. Under his and Jorunn Stamnæs’ supervision

I’ve learned about the fascinating world of immunology research. Most of my time spent in

the research group however, is focused on minute details of mucosal cells. To better get an

understanding of the clinical aspects of coeliac disease research, I chose the topic of screening

for coeliac disease, a very interesting topic when it comes to the future of coeliac disease.

While writing this thesis I have received great guidance from my supervisors and I am very

grateful for their help.

5

CONTENTS

Abstract ...................................................................................................................................... 2

Sammendrag ............................................................................................................................... 3

Foreword .................................................................................................................................... 4

Introduction ................................................................................................................................ 7

Aim ......................................................................................................................................... 7

Coeliac Disease ...................................................................................................................... 7

Prevalence .......................................................................................................................... 7

Genetic and Environmental Background ........................................................................... 7

Pathophysiology ................................................................................................................. 8

Clinical Picture ................................................................................................................... 9

Diagnostic Work-Up .......................................................................................................... 9

Requirements for Diagnosis ............................................................................................. 10

Developing Diagnostic Opportunities .............................................................................. 10

Treatment ......................................................................................................................... 11

Prognosis .......................................................................................................................... 11

Age of Disease Development and Age of Diagnosis ....................................................... 12

Screening .............................................................................................................................. 12

The Burden of Overdiagnosis and Medicalization ........................................................... 15

Screening for Coeliac Disease .......................................................................................... 16

Methods .................................................................................................................................... 17

Results ...................................................................................................................................... 17

Screening of Coeliac Disease in the General Population ..................................................... 17

In Children ........................................................................................................................ 17

In Adults ........................................................................................................................... 19

Screening for Coeliac Disease in At-Risk Groups ............................................................... 20

In Type 1 Diabetes ........................................................................................................... 20

Autoimmune Thyroid Disease ......................................................................................... 21

IgA Deficiency ................................................................................................................. 21

Relatives ........................................................................................................................... 21

Down Syndrome ............................................................................................................... 22

Turner Syndrome .............................................................................................................. 22

Irritable Bowel Syndrome ................................................................................................ 22

6

Iron Deficiency Anaemia ................................................................................................. 23

Dental Enamel Defects ..................................................................................................... 23

Other Conditions .............................................................................................................. 23

Guidelines ............................................................................................................................. 23

Economical Aspects ............................................................................................................. 25

Ethical Considerations .......................................................................................................... 26

Socioeconomic Differences .............................................................................................. 26

Quality of Life .................................................................................................................. 26

Do No Harm ..................................................................................................................... 27

Beneficence ...................................................................................................................... 27

Fair Use of Resources ...................................................................................................... 28

Discussion ................................................................................................................................ 28

Future Considerations .......................................................................................................... 31

New Diagnostic Approaches ............................................................................................ 31

Changing Prevalence ........................................................................................................ 31

Developing Therapeutics .................................................................................................. 31

Conclusion ................................................................................................................................ 32

References ................................................................................................................................ 32

7

INTRODUCTION

Aim

Coeliac disease is a common disease of the small intestine, yet most individuals with coeliac

disease remain undiagnosed. Living with unrecognized coeliac disease could potentially have

a negative impact on health and quality of life. The aim of this thesis is to provide an overview

of the possibility of screening for coeliac disease in Norway, taking into account medical,

ethical, economical and practical considerations in Norway as of 2021.

Coeliac Disease

Prevalence

Coeliac disease (CD) is the most prevalent autoimmune disease of the small intestine. The exact

prevalence of the disease is unknown, but estimates suggest that roughly 1-2% of the global

population is suffering from CD, with figures of 1.4% (95% CI, 1.1%, 1.7%) if using serological

results or 0.7% (95% CI, 0.5%, 0.9%) if only using biopsy-confirmed CD (1). The incidence of

CD is increasing, and it seems to be a true rise and not just increased awareness and detection

among clinicians (2). Despite this, the majority of CD patients in most populations remain

undiagnosed (3). As CD can present in all age groups and is a lifelong disease, there is a

substantial number of undiagnosed CD patients in all age groups (4).

Genetic and Environmental Background

CD is a multi-factorial disease that develops in genetically predisposed individuals. There is a

strong association with certain HLA allotypes. Especially HLA-DQ2.5, which 90-95% of all

CD patients possess, the remainder of the patients carrying either HLA-DQ8 or HLA-DQ2.2

(3). Roughly half of the Danish population carries HLA-DQ2.5 and/or HLA-DQ8 (5), which

tells us that most of the people with the genetic potential of getting coeliac disease, will not

suffer from coeliac disease. It is reasonable to assume that similar numbers would be mirrored

in the genetics of the Norwegian population. Interestingly there is a dose effect of HLA-DQ2.5,

with homozygous DQ2.5 carriers having a CD risk of up to 30%, while heterozygous

individuals have a risk of getting CD of only 3% (6, 7). Even though these HLA haplotypes are

central to CD pathogenesis, they still only contribute about 35-40% of the genetic risk in CD

(7). GWAS studies have provided several additional loci with a minor additional risk

component, most of them involved in the immune system, such as T-cell regulating genes (6).

8

Apart from genetics factors, unknown environmental factors also contribute to the mounting of

an immune response that is triggered by the ingestion of dietary gluten (2).

Pathophysiology

The major environmental factor, gluten proteins, have special properties. Gluten is a collective

term used for storage proteins found in the cereal grains wheat, barley and rye. Gluten proteins

are enriched in the amino acids proline and glutamine, which makes them partly resistant to

gastric, pancreatic and brush-border peptidases, rendering peptides as large as 33 amino acids

or longer free to access the lamina propria (2). Via either trans- or paracellular routes (2), these

peptides enter the lamina propria and trigger an immune reaction in individuals with CD. The

major autoantigen (“self” derived antigen) in CD, is transglutaminase 2 (TG2). TG2 is a protein

produced in the cytosol of the cell, and it has a broad tissue distribution (8). TG2 deamidates

peptides, including gluten peptides (2). This deamidation process increases the binding of

gluten derived peptides to the abovementioned HLA-DQ2 or HLA-DQ8 molecules, allowing

for T-cell recognition of the peptides. Because T-cells go through a more strict selection and

elimination process when maturing in the thymus, than what the B-cells go through, it is rarer

that T-cells display strong reactivity against the body’s own proteins. Gluten derived proteins

however, are not of the body’s own making, and T-cells may recognize them correctly as

foreign, in contrast to the enzyme TG2, which is a major target of plasma cells in CD.

Normally when B-cells mature into plasma cells and produce antibodies, they need help from

T-cells. This happens when B-cells present what they have captured, after some processing, as

peptides on HLA-molecules on the cell surface. T-cells with a T-cell receptor specific for the

antigen presented on a given B-cell, will help that B-cell mature into a plasma cell. How this

process occurs in CD so that antibodies against gluten-derived gliadin and the autoantigen TG2

may be formed however, is somewhat unknown. Still, T-cells specific for gluten-derived

peptides, and B-cells specific for TG2, seems to be central in the mounting of an immune

reaction in CD (8). Furthermore, in manifest CD these gluten specific T-cells reside in the gut

and release proinflammatory cytokines upon ingestion of gluten containing foods (8).

Despite the autoantibodies (antibodies targeting “self”) themselves not being known to play a

major part in the disease yet, recently Høydahl et al (9) showed that plasma cells are the main

gluten-peptide presenting cell in the gut of CD patients, suggesting their importance in antigen

presentation and T-cell activation. Other autoantibodies seen in some sub-groups of patients

might contribute to extra intestinal manifestations such as gluten ataxia or dermatitis

herpetiformis (2).

9

One of the hallmarks of CD is intraepithelial lymphocytosis. This is probably an innate immune

response in the epithelial compartment of the intestinal villi. The intraepithelial lymphocytes

express the NK-T-Cell receptors NKG2D and NKG2A which recognize stress induced

glycoproteins on enterocytes (2). Cytokines from other CD4+ T-cells regulate the action of these

cytotoxic intraepithelial cells. This results in secretion of cytotoxic molecules and killing of

epithelial cells (8). The activation of CD4+ T-cells and their subsequent activation of cytotoxic

intraepithelial lymphocytes connects the adaptive immune response in the lamina propria and

the innate immune response of the epithelium, both seemingly essential parts in CD pathology

(2). This combined adaptive and innate immune response also seems to be responsible for the

major tissue remodelling seen in the coeliac lesion, with crypt hyperplasia and atrophy of villi

effectively rendering the gut “flat” with a substantially decreased surface area, and thus

decreased ability to absorb nutrients (2, 6).

In addition to the presence of CD4+ T-cells specific for gluten derived peptides, the untreated

coeliac lesion is packed with plasma cells in the lamina propria, including the plasma cells

producing autoantibodies targeting TG2 (10, 11). These cells and their antibodies drop in

number following the patient starting a gluten free diet (6).

Clinical Picture

The disease primarily affects the small intestine which leads to the classical CD presentation of

a child presenting with malabsorption, steatorrhea, diarrhoea, failure to thrive and weight loss.

This picture has increasingly been replaced by “non-classical” CD patients, presenting in all

age groups with vague symptoms such as anaemia, IBS-like symptoms, chronic fatigue,

osteoporosis and even asymptomatic (2, 12). These varying and vague symptoms contribute to

a substantial decrease in the quality of life in coeliac patients prior to diagnosis (13).

Diagnostic Work-Up

Traditionally the diagnosis of CD has been based on the combination of a positive serology and

a duodenal biopsy showing inflamed mucosa with major tissue remodelling (12). Serological

tests measuring IgA-autoantibodies against TG2 are highly sensitive, around 95% in untreated

CD and highly specific with a specificity of 95% or higher (14), the exact numbers depending

on where the test limit is set, as the likelihood of a true positive test increases with higher titres,

and the setting in which the test is developed. The high sensitivity and specificity combined

with the relative inexpensiveness compared to biopsies or the measurement of endomysial

antibodies, makes measurement of IgA-TG2 antibodies a good first-line screening tool for CD

(2). An important exception however, is the 2% of CD patients with IgA-deficiency, where tests

10

based on IgA-TG2 will be negative (12). Therefore, total IgA is typically used in conjunction

with IgA-TG2 antibodies. Alternatively other autoantibodies such as IgG-TG2 could be used,

however in a low risk setting where the pre-test probability is low, such as in the general

population, combining several of these autoantibody tests to increase sensitivity, generally

reduces the positive predictive value, while having a limited impact on sensitivity (14). When

it comes to the timing of testing, it is preferable that all serological diagnostic tests are done

while the individual is still on a gluten containing diet. This is due to antibody titres dropping

upon the patient starting a gluten free diet (7).

Biopsy samples are gathered using upper endoscopy, going via the stomach to the duodenum.

Several biopsies are taken, and these are analysed by a pathologist who grade them on a

categorical scale based on tissue architecture and the presence of certain inflammatory cells.

This scale ranges from normal mucosa, via intraepithelial lymphocytosis to more definitive

signs of disease such as villous atrophy. More quantitative measures of histology have been

suggested in an effort to make the criteria of disease more objective, but these are time

consuming compared to the more subjective, traditional histological evaluation (7).

Requirements for Diagnosis

In general there is a lack of unified guidelines regarding the diagnostic requirements of CD.

Development has come in the diagnostic work-up of children in the last few years with the

European Society Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)

deeming serological results sufficient to diagnose paediatric CD when IgA-TG2 antibody titres

exceed 10 times the upper limit of normal (15). Notably however, while the European

ESPGHAN recommends serology as sufficient to diagnose CD, children in USA needs a biopsy

(16). A purely serology based approach spares the children the general anaesthesia often needed

to perform endoscopy. Still, ESPGHAN does recommend biopsies when the titres are in the

low positive range (15). There is discussion on whether a serology only approach could be wise

in adults as well, with a UK study finding a positive predictive value of 99% for a 10-fold

increase in anti-TG2 approach, albeit in a pre-selected at-risk group (17). Still, the duodenal

biopsy remains the gold standard for diagnosing CD, and with an exception of Finnish

guidelines (16), a diagnosis in adults is generally based on the combination of clinical,

serological and histopathological data (7).

Developing Diagnostic Opportunities

Other tests are on a more experimental stage at the moment, for instance saliva testing for IgA-

TG2 autoantibodies could potentially present a simple, non-invasive and inexpensive option in

11

the future CD diagnostic approach (7). Another promising test is a test based on measuring the

T-cell immunity against gluten. A tetramer molecule consisting of complexes of HLA with

gluten peptides bound, using only blood, is a highly sensitive and specific measure of CD, even

when the individual is on a gluten free diet (18, 19). Currently however, this test is at too high

a cost to be effectively used in screening programmes (3).

Treatment

The treatment of CD is first and foremost lifelong strict adherence to a diet free of any gluten.

Following this treatment symptoms tend to start disappearing in days to weeks (2). Healing of

the small intestinal mucosa takes longer, with about half of the patients in a Norwegian cohort

normalized within 1 year (20). In addition to a gluten free diet treatment typically includes

screening for nutritional deficiencies upon diagnosis, and a consideration of dietary

supplementation of among others iron, folate and vitamin B12 (7). Dietary education by a

doctor or dietitian is central. Because fibre and iron is especially hard to replace on a gluten

free diet, education is focused on good alternatives providing a balanced high fibre diet (2).

Decreased bone density is also a risk in untreated CD, and screening for low bone density is

relevant in newly diagnosed patients above 55 years of age (2). Regular follow up by a health

professional is also a part of good CD treatment.

Challenging however, is the treatment of the roughly 20% of patients who are unresponsive to

a gluten free diet (2). In these cases the diagnosis is often revisited to look for other

explanations, especially when serology is missing. Often inadvertent gluten ingestion is the

culprit. There is debate whether routine follow up histology should be done.

Prognosis

Even though the majority of CD patients recover when put on a gluten free diet, when looking

at population based studies, there is an association between CD diagnosis and increased

mortality. This was recently shown in a large Swedish cohort, where all-cause mortality was

increased across all age groups, with a hazard ratio of 1.21 (95% CI, 1.17-1-25), with largest

effects seen in patients diagnosed in young adulthood, and especially the first year after

diagnosis (21).

One feared association with CD is malignancies of the gut, in particular enteropathy-associated

T-cell lymphoma. While it could be argued that the absolute risk is low, the relative risk is very

high. In a recent Dutch study the relative risk of all T-cell lymphoma in CD patients was 35.8

(95% CI, 27.1, 47.4). The largest risk among these patients was in males over 50 years of age,

where the absolute risk of T-cell lymphoma was 4.3%. Although the highest risk was at the

12

time of CD diagnosis, the increased risk remained also 1 year after diagnosis (22). In line with

this, a Swedish study found that the risk of lymphoproliferative malignancies in CD is

associated with results of follow-up biopsies, with persistent villous atrophy increasing the risk

(23).

Age of Disease Development and Age of Diagnosis

Important in detection of disease is knowing at what age it typically appears. As mentioned

above CD is diagnosed at all ages, many as adults, and in adults it has a peak of diagnosis

between 40 and 60 years of age (24). However, some prospective studies in children suggest

that most seroconvert in early childhood before school age (25). Prospective studies of CD

development in adults are few, still some evidence suggests that very few individuals

seroconvert and get CD in adulthood, with an American study reporting a cumulative incidence

of 0.06% (95% CI, 0.01%-

0.11%) during a ~10 year

period following 15,398

initially seronegative

adults (26). This suggests a

possible time lag between

true disease onset and

disease detection,

something which is

entirely possible given the

extent to which CD is

underdiagnosed.

Screening

Screening in General and History

Screening is based on the idea of detecting disease or precursors to disease at an early stage,

thus facilitating better treatment or even prevention. This does not necessarily mean diagnosing

only asymptomatic individuals, although they could be asymptomatic, rather it means testing

people who would not otherwise be tested at the time. That is, the threshold for testing is

substantially lowered so that the same level of help seeking behaviour is not needed from the

individual, potentially diagnosing individuals who would otherwise be lost to the system.

Figure 1: A hypothetical model showing how delayed diagnosis could explain why

CD is clinically detected at all ages, while prospective studies primarily detect CD

in childhood.

13

Although screening sounds simple in principle, difficulty arises with avoiding harm to patients’

not needing treatment.

Around the same time that new-born screening for phenylketonuria started (27), Wilson and

Jungner in 1968, in their landmark paper, outlined 10 basic principles of screening that still

serve as the foundations for what conditions should be screened for today.

THE 10 PRINCIPLES OF SCREENING:

Wilson and Jungner (28)

(1) The condition sought should be an important health problem.

(2) There should be an accepted treatment for patients with recognized disease.

(3) Facilities for diagnosis and treatment should be available.

(4) There should be a recognizable latent or early symptomatic stage.

(5) There should be a suitable test or examination.

(6) The test should be acceptable to the population.

(7) The natural history of the condition, including development from latent to declared

disease, should be adequately understood.

(8) There should be an agreed policy on whom to treat as patients.

(9) The cost of case-finding (including diagnosis and treatment of patients diagnosed)

should be economically balanced in relation to possible expenditure on medical care as a

whole.

(10) Case-finding should be a continuing process and not a "once and for all" project.

Along with these principles Wilson and Jungner also define different approaches to screening,

such as mass screening, where no pre-test selection is made, selective screening, where high-

risk groups are identified and tested, multiple screening where two or more screening tests are

combined and surveillance where focus is made on the continuous observation of persons (28).

These different approaches impacts the pre-test probability of disease. Whereas mass screening

generally comes with a relatively low pre-test probability, high-risk groups will have an

increased pre-test probability, and multiple screening typically includes applying one test to the

general low risk group, using that test to select which individuals should undergo a second test.

Factors such as the prevalence of the disease and properties of available diagnostic tools impact

which approach is better for a given disease.

14

For instance when detecting every single case is of the utmost importance, for example fatal

communicable diseases, the ideal test would have a very high sensitivity. Sensitivity is measure

of the extent to which a test is able to identify individuals with the condition being tested for.

Using the table below, sensitivity can be calculated using the following equation:

𝑆𝑒𝑛𝑠𝑖𝑡𝑖𝑣𝑖𝑡𝑦 = 𝑃(𝑃𝑜𝑠𝑖𝑡𝑖𝑣𝑒 𝑆𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔|𝐷𝑖𝑠𝑒𝑎𝑠𝑒) =a

a + c

Increasing the sensitivity of a test however, often means lowering the threshold of what is

considered a positive result effectively lowering the specificity of the test, which is the

test’s ability to identify healthy individuals as such.

𝑆𝑝𝑒𝑐𝑖𝑓𝑖𝑐𝑖𝑡𝑦 = 𝑃(𝑁𝑒𝑔𝑎𝑡𝑖𝑣𝑒 𝑆𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔|𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝐹𝑟𝑒𝑒) =d

b + d

Interpreting a test result in clinical practice however, depends also on the pre-test probability.

In a completely unselected population this would be lower than if the test is applied to a

selected group such as individuals with symptoms indicative of the condition. This, together

with measures of sensitivity and specificity affects the positive and negative predictive values,

which are often more practical values in the clinic. The positive predictive value is a measure

of the probability of a positive test being a true positive.

𝑃𝑜𝑠𝑖𝑡𝑖𝑣𝑒 𝑃𝑟𝑒𝑑𝑖𝑐𝑡𝑖𝑣𝑒 𝑉𝑎𝑙𝑢𝑒 = 𝑃(𝐷𝑖𝑠𝑒𝑎𝑠𝑒|𝑆𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔 𝑃𝑜𝑠𝑖𝑡𝑖𝑣𝑒) =a

a + b

As seen in the equation above, when a disease is very rare, then the positive predictive value

could be quite low despite seemingly high sensitivity and specificity. For instance in the case

of a low pre-test probability, say 1/100,000, and both a sensitivity and a specificity of 99%,

this would mean a positive predictive value of only ~1/1000. Thus the vast majority of

positive results would only yield unnecessary worry. On the other hand, in pre-selected

groups such as at-risk groups in a screening programme, the positive predictive value of a test

would be higher than for the general population. Along the same lines, the negative predictive

value, which measures the probability of a negative screening test being a true negative, is

also affected by the pre-test probability.

𝑁𝑒𝑔𝑎𝑡𝑖𝑣𝑒 𝑃𝑟𝑒𝑑𝑖𝑐𝑡𝑖𝑣𝑒 𝑉𝑎𝑙𝑢𝑒 = 𝑃(𝐷𝑖𝑠𝑒𝑎𝑠𝑒 𝐹𝑟𝑒𝑒|𝑆𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔 𝑁𝑒𝑔𝑎𝑡𝑖𝑣𝑒) =d

c + d

Disease Disease Free

Screening Positive a b

Screening Negative c D

15

Here if the disease is rare as in the case above, the negative predictive value will be higher.

All these different properties of diagnostic tests together says something about the strengths

and weaknesses of the tests and open up for different approaches. Ideally the test would have

perfect sensitivity and specificity, however this is rarely possible and more often there is a

trade-off where increasing one decreases the other. Thus, it is often possible to adjust a test so

that it better fits the screening program, whether that is making sure no cases are missed, or

avoiding too much resources spent on false positives. Important when it comes to adjusting

the properties of a test is that it is adjusted to fit the population it is being used on. Challenges

could arise if a test developed in a high-risk setting, where distinguishing cases could

potentially be clearer, is being brought to the generally low-risk setting of a screening

programme.

Screening Programmes in Norway

In Norway different types of screening approaches are used. The mass screening approach is

used for new-borns, testing for a range of inherited diseases such as phenylketonuria. With

increasing diagnostic and therapeutic opportunities, the Norwegian new-born screening

programme has grown to include 25 diseases as of 2020 (29). Another example of an approach

seen in Norway is the widespread testing of contacts of confirmed cases during the COVID19

pandemic. This is an example of high-risk screening, where tests are used on asymptomatic

individuals with an increased risk of infection, albeit not necessarily in an effort to treat the

index patient herself, but rather to stop the spread of infection. A different screening effort also

seen in Norway is the surveillance approach used in the cervical cancer screening programme

for women aged 25 – 69 years (30).

The Burden of Overdiagnosis and Medicalization

When screening for a disease, one runs the risk of expanding the definition of disease,

diagnosing and treating individuals who would never have actually suffered from the disease.

This gives rise to public debate, an example of which in Norway is the large scale screening of

breast cancer in women. The substantial increase in incidence of breast cancer after screening

programmes were initiated (31) has led to some experts calling for the end of the screening

programme, claiming it does more harm than good (32). A related challenge to screening is

medicalization, the process by which human problems are increasingly viewed as medical

issues to be fixed through medical therapy (33). A main driver in the medicalization process is

thought to be the pharmaceutical industry pushing towards increasing diagnosis and treatment

of human problems thereby increasing profits (33). Regarding this, the lack of a medicalization

16

incentive for the pharmaceutical industry, given that for the time being a gluten free diet is the

main treatment of CD, could be another potentially contributing factor when comparing CD to

other diseases that are not underdiagnosed.

Screening for Coeliac Disease

Widespread screening of all children for CD is not in use in Norway as of January 2021, nor

has it been screened for in such a way in Norway. Screening for CD agrees with most of the

criteria outlined by Wilson and Jungner, possibly with the exception of the natural course of

the disease from the asymptomatic to the clinically obvious disease being well known, and in

relation to this whether the value of an early diagnosis outweighs the costs and societal burden

of a screening program.

Interestingly, population based screening studies have found a large discrepancy between the

number of diagnosed CD cases and the true prevalence of CD, with Scandinavian studies

showing a combination of active case finding and screening of at-risk groups yielding the

diagnosis of CD in roughly one third to half of the actual cases in the population (34). The

variable presentation of CD probably contribute to this under-diagnosis.

To combat the underdiagnosis there are three general approaches to increase detection. The first

is active case finding, which to some extent is what is traditionally practised by medical doctors.

The second is screening of at-risk groups, such as people with conditions associated with CD.

The third and most demanding approach is mass screening of the whole population. These

options obviously differ in their yield and cost, with the latter approach uncovering more

undiagnosed patients, while at the same time costing more than the more targeted approaches.

Principles such as multiple screening or surveillance could be baked into either of these

approaches.

Of note in screening for CD is the implications of the recent developments in diagnostic

opportunities and criteria. The movement towards a more serology only based approach in most

patients would make screening easier, as only a fraction of individuals, those with low positive

values, would have to undergo endoscopy. Skipping the endoscopy requirement in many

patients effectively makes a potential screening programme less costly and demanding and thus

more doable.

17

METHODS

I took a broad approach to literature in this narrative review. At first a detailed reading of

relevant coeliac disease guidelines from authorities on coeliac disease was done. Then a

revision of screening in general, largely based on the World Health Organization’s criteria for

screening. Thereafter the main focus was on performing a non-systematic literature review of

coeliac disease screening trials using the search engine PubMed, covering articles including the

terms “screening”, “prevalence” or “incidence” in addition to “coeliac disease” or “celiac

disease”. To better cover the broader approach governmental reports and policies relevant to

the financial situation of coeliac disease patients in Norway were included. On that topic also

articles discussing economical aspects of screening programmes were searched for using

PubMed. Literature on screening in general and discussion of other screening programmes and

their challenges in Norway was included to more fully frame the picture in which a potential

coeliac disease screening programme would have to enter.

RESULTS

Screening of Coeliac Disease in the General Population

In Children

Screening all children for particular diseases is already done in Norway, especially in the new-

born period. As CD is a maladaptive response to gluten however, screening for CD in new-

borns before gluten exposure is of little value. Screening soon after though, in toddlers on a

gluten containing diet, is a topic of some debate. In general the costs per detected case of CD

increases as screening strategies aim for identifying more individuals. This is why guidelines

attempt to define smaller at-risk groups where the argument for a potential benefit is more clear

cut.

Yet, some studies have looked at the possibility of mass wide population screening of children

for CD. In San Marino a screening programme for CD was worked in during well-child visits

of children at 6, 10 and 14 years of age at the general paediatrician from 1993 to 2009. This

study showed a high willingness among parents and children to participate in the screening and

give a blood sample (87%). This yielded a final diagnosis of biopsy confirmed CD in 0.8%,

although this hides that the number was higher in the last years of the study as the serological

method was changed from anti-gliadin-antibodies (0.7%) to anti-TG2-antibodies (1.8%).

Biopsy was done when an array of serological tests suggested CD, and confirmed the diagnosis

18

in as many as 42 out of 44 serologically positive patients. At an initial low cost of only the

serology sample analysis, and with the high compliance, and also the high positive predictive

value of the serology results, such a screening programme showed promise in San Marino (35).

A similar study in Finland included unselected schoolchildren and adolescents, median 12 years

of age, showed that roughly 1% had biopsy proven CD, possibly more if all with positive

serology had attended follow-up biopsy. This was in a cohort where at the time of sampling no

one was diagnosed with CD. Interestingly, about one third of the subjects diagnosed with CD

had no symptoms or risk factors, meaning they would likely not have been picked up by other

approaches such as active case finding or at-risk group screening (36). Another observation

taken from the study was that a minor proportion of the cohort, 5 out of 3627 had initially

positive autoantibodies, that went away in the second sample taken years later despite eating a

gluten containing diet, they were thus transient seropositive.

A more recent study of mass screening of children 1 – 17 years old in the USA showed a high

prevalence (2.4% based on serology) of undiagnosed CD, while at the same time the study did

not find an association between the presence of 1 or more symptoms at initial screening and

serology results. In fact the majority of seropositive children did not report any symptoms

(~70%), nor any family history of CD (~90%) (37). A similar prevalence of CD in

asymptomatic children has been seen in other studies (38). Notably children aged 6-13 had

nearly twice the risk of getting a positive serology result when compared to younger children

or older adolescents, suggesting primary school aged children as a potential target group of

screening (37).

Others have called for an alternative two step approach to screening the general population for

CD, namely initial screening for the risk associated HLA-DQB1*02:01 (OR = 10.28 (95% CI,

4.49, 23.49)) (39). As more than 90% of CD children carries this allele, this would allow for a

more targeted follow up serological testing, making a surveillance based screening programme

a more realistic option. Generally HLA typing is expensive, so the utility of this approach would

necessarily be based on savings related to the surveillance of only HLA-DQB1*02:01-positive

individuals (39). Other versions of this could be of use, depending on the wanted sensitivity

and specificity, for instance testing both HLA-DQ2 and HLA-DQ8 would yield a very high

negative predictive value, as <1% of CD are negative for both (12). Although the positive

predictive value of the initial test alone would be poor, with the prevalence of DQ2 in the

general population between 0% and 40%, and DQ8 between 0% and 20% (12), the positive

19

predictive value of a positive serological test in this pre-selected group would be higher than in

the general population.

In Norway HLA-screening of 46 939 new-borns for HLA types DR4-DQ8/DR3-DQ associated

with type 1 diabetes (T1DM) was used in a study of T1DM development. As CD shares this

genetic risk, old samples were analysed retrospectively from those consenting among the HLA-

positive individuals. These at-risk children were tested several times in early childhood and

25/220 were identified to have CD, 17 of these seroconverted before age 35 months. Although

participation in this follow up study could have been biased towards those parents suspecting

CD, as only a little under half of the 501 invited accepted the invitation, this two-step approach

still showed promise in this Norwegian cohort. Adding to that is the fact that 12 of the 25

identified CD cases in this study had not been identified clinically outside of this study, several

of them seropositive years before they got the diagnosis through this retrospective study (40).

On a related note a European study following toddlers with either HLA-DQ2 or HLA-DQ8

found that ~5% developed CD by the time they were 5 years old, sub group analysis however,

showed that as many as 27% of those homozygous for HLA-DQ2 developed CD in the same

time period (41).

These studies of screening for CD in children collectively show that there is a mountain of

undiagnosed children out there, likely also in Norway. A not insignificant number of them were

not part of any recognized risk group nor symptomatic, thereby only detectable through mass

screening. Some limited evidence suggest a high incidence in the age group 6-13 year olds,

suggesting a potential target group for screening approaches.

In Adults

Still, there is no consensus on when the true incidence peak is in CD. As it is a lifelong disease,

and as mentioned above majorly underdiagnosed, data on when patients are diagnosed does not

necessarily reflect age of onset. Nonetheless this means that uncovering undiagnosed CD in

adults is a possibility for a screening programme. It does however depend on the population, as

a study in Japan in 2020 demonstrated, where there were almost no detected cases of CD among

adults, with only 0.19% seropositive individuals (42). In such cases screening is certainly of

lesser value. This is opposed to a 2015 study of the adult Danish population where 56/2297

(2.4%) participants were seropositive, albeit a lower percentage had biopsy proven CD, yielding

a screening based prevalence of CD of 479/100,000 in (95% CI: 197-761) (43). This was

roughly ten times the number of patients in the Danish National Patient registry, meaning the

degree to which CD was underdiagnosed was substantial. A follow up analysis showed that

20

participants were satisfied with being part of the screening for CD, and the majority of the

diagnosed individuals felt better on a gluten free diet, despite many not showing clear symptoms

before the diagnosis (44).

More telling is probably the data from a large international mass screening study of ~30 000

children and adults in Europe which revealed large variances across different countries, but an

average prevalence of 1%, which increased with age (4). A similar rate of seropositivity has

been seen in adults in Norway (45). Similarly to the abovementioned Danish study, this

European study also showed a large degree of underdiagnoses in all countries, with previously

diagnosed CD patients only constituting from 6% (Italy) to 24% (Finland) of the diagnosed.

Although this study is from a few years back and was done with archived samples and published

in 2010, the results imply that there was at the time a high frequency of undiagnosed CD in the

adult population all across Europe that could be detected through screening.

Screening for Coeliac Disease in At-Risk Groups

In Type 1 Diabetes

Whereas recommending screening of the general population requires a very strong conviction

of the benefits, given the amount of resources such a programme would demand, screening of

at-risk sub-groups could potentially be an easier case to argue for advocates of CD screening.

At-risk groups often discussed are individuals with diseases and conditions that for some reason

are associated with CD, thereby allowing for improved case finding. Type 1 diabetes (T1DM)

is one such disease often brought up in the discussion of at-risk screening for CD. Like CD,

type 1 diabetes is also an autoimmune disease, and the two diseases share genetic risk (3). Thus

many studies have looked at this group of patients as a potential at-risk group worthwhile

screening for CD. While typical estimates suggest that roughly 5% of T1DM patients have CD

(3), this number could be up to three times higher if the individual has additional risk factors

such as being diagnosed with T1DM before 4 years of age and the individual being a girl (46).

A Swedish study looking at newly diagnosed children with T1DM found that 3% had

concurrent, undiagnosed CD, and within 5 years this number increased to ~ 9% (47), most

within the first 2 years, making a strong argument for at-risk group screening of T1DM children

in what is presumably a similar population in Norway.

Concerns regarding the consequences of undiagnosed CD in T1DM patients include the reduced

bone mineral density seen in late CD detection in these patients (48). In addition, signs of both

increased rates of retinopathy, nephropathy and poor glycaemic control have been reported in

21

T1DM patients with unrecognized CD (49), and it seems that these patients at least do not show

a decreased quality of life upon starting a gluten free diet after being diagnosed with CD through

screening (49).

Autoimmune Thyroid Disease

This group of diseases containing Graves and Hashimoto’s disease is associated with CD. The

association is believed to be caused by shared genetic risk through HLA-DQ2 and HLA-DQ8

(48). Whether there is a causal relationship regarding which of autoimmune thyroid disease and

CD comes first in individuals suffering from both, remains unclear. The potential value in

screening for CD in autoimmune thyroid is less clear than for T1DM. Studies have given

varying results, with a rate of new CD diagnosis in ~ 1% - 3% of screened individuals with

autoimmune thyroid disease (50, 51).

IgA Deficiency

Interestingly, there is an association between IgA deficiency and CD which may seem

paradoxical given the assumed role of IgA-TG2 in CD pathogenesis (52). Even more interesting

from a Norwegian perspective is that one of the largest studies done on this is a Swedish study

from 2014, where Ludvigsson et al reported that in their study registry based study, 6.7% of the

2100 individuals with IgA deficiency had CD, compared to only 0.19% in the control group

(53). Although this study was not a screening study, and there could be differences in how good

the Swedish health care system has been at detecting CD in the different groups, this 35-fold

higher prevalence of CD in individuals with IgA deficiency is noteworthy. Also the observed

6.7% prevalence in IgA deficiency fits well with observations done in other countries, with

typical estimates of ~6% (52). Thus, even though IgA deficiency is a rare condition, with an

estimated frequency of roughly 1:600 in a Western population (53), the strong association with

CD impacts diagnostic work-ups for CD so that they typically include either total IgA or

somewhat disease specific IgG antibodies.

Relatives

One of the more promising at-risk groups when it comes to looking for CD is close relatives of

index patients. Given the abovementioned genetic factors contributing to the disease, there is

reason to believe that some of the genetic factors that contribute to disease in the index patient

is also present in close relatives. For instance identical twins of index cases have an ~80% risk

of getting CD (34). In line with this, first degree relatives have also been reported to have a

substantially increased risk of developing CD, with figures varying from 4 – 15% of first degree

relatives identified as CD patients, and second degree relatives also at an increased risk (48).

22

Down Syndrome

An at-risk group where evidence of screening identifying more patients is stronger, is children

with Down syndrome. The official guidelines of The European Society Paediatric

Gastroenterology, Hepatology and Nutrition (ESPGHAN) defines Down syndrome as a

condition suggesting CD in a patient. A recent study showed that an active approach increased

case finding substantially (54), suggesting screening of this group of patients to be very

effective. Moreover, in Sweden Mårild et al found a 6-fold increased risk for CD in individuals

with Down syndrome compared to controls (55), indicating an association potentially worth

screening based on. Swigonski et al however, have criticized screening of asymptomatic Down

syndrome patients for CD, concluding that it reduces overall quality of life, and that the costs

are beyond reasonable per life-year gained (56). This American study focused mainly on

lymphoma as the CD complication that could shorten the lives of individuals with Down

syndrome, and factors such as the lower life expectancy in Down syndrome, combined with the

abovementioned late onset of lymphoma in CD, supports this conclusion.

Turner Syndrome

Another chromosome abnormality associated with CD is Turner syndrome (57). As Turner

syndrome is an inborn chromosome abnormality, it necessarily precedes CD. The association

seems to increase with age as new cases of CD are diagnosed. In a Swedish population the risk

of CD in individuals with Turner syndrome ranged from a twofold increase compared to the

general population in the first 5 years of life, to a fivefold increase in those 10 years of age or

older (57), arguing for active case finding of CD in individuals with Turner syndrome.

Irritable Bowel Syndrome

A common functional disorder of the gut is irritable bowel syndrome (IBS). Patients often have

abdominal pain related to food intake, and some have reported responding to a gluten free diet,

often getting the diagnosis of non-coeliac gluten sensitivity (48). A recent double-blind,

crossover challenge study from Norway did however, point out another common wheat

component, fructans, not gluten, as the likely culprit in individuals with non-coeliac gluten

sensitivity (58). Still, there is a group of patients with IBS that has actual CD, as a meta-analysis

showed a fourfold increased frequency of CD in IBS patients compared with controls (59). In

line with this, guidelines for investigating IBS include testing for CD (60). On a related note

ESPGHAN recommends testing for CD in patients with symptoms overlapping with IBS, such

as chronic abdominal pain (15).

23

Iron Deficiency Anaemia

One common presentation of CD is iron deficiency anaemia. In a recent systematic review

Mahadev and co-authors showed that around 1 in 31 patients identified to have iron deficiency

anaemia also had CD, possibly higher if only using the high quality studies, arguing that

screening for CD in iron deficiency anaemia would be worth the effort (61).

Dental Enamel Defects

There is an association between dental enamel defects and CD. A study in Egypt found that as

many as 18% of children with dental enamel defects have CD, compared to only 1% in the

control group. By far the majority of the children with dental enamel defects had CD. The

children with CD also tended to have more serious dental lesions (62).

Other Conditions

Several other conditions have been studied in relation to CD. As CD is a disease triggered by

ingestion of certain foods, a possible link with eating disorders have been hypothesized. Several

studies looking at associations between CD and eating disorders have not however, found

convincing evidence of such a relationship, reporting a similar presence of CD in these sub-

groups as in the general population (63, 64). Other studies looking at a relationship between

CD and overweight has shown mixed and unconvincing evidence of an association (65, 66).

Another condition where screening for CD could be of increased value compared to screening

in general, is in children with autism spectrum disorder. There is little data, but an Italian study

from 2016 showed a markedly higher prevalence of CD in children with autism spectrum

disorder compared to Italian children in general (67). At the present however, there is too little

evidence to conclude. There also seems to be an increased frequency of CD among patients

with IgA nephropathy (68). In line with this data from Turkey indicate that there could be an

overrepresentation of unrecognized CD among patients suffering from chronic kidney disease

in general (69). Lastly in some countries CD screening has been applied systematically to

children with short stature yielding good results (70).

Guidelines

Different authorities on CD have published their own guidelines on when to test for CD. In

general the different guidelines support a low threshold for testing and case-finding, albeit not

fully supporting population wide screening. Included here are some of the at-risk groups where

there is broader support among several of the different institutions. The recommendations from

the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)

24

are strictly paediatric guidelines, while the others included cover all age groups. Contrary to the

other guidelines included, the British Society of Gastroenterology in their guidelines, only

recommends testing in symptomatic patients or when CD is already suspected (71).

Although some of the varying recommendations could be because of different use of disease

categories, there is still some disagreement on which conditions meet the threshold for CD

testing in the absence of obvious symptoms. Several also recognize extra conditions where tests

should be done if symptoms are present. The following table includes conditions for which the

different guidelines recommend at least considering CD testing, even in the absence of

symptoms. Not part of this table are typical gastrointestinal symptoms which are widely

regarded as an indication for testing.

Non exhausting summary of organizations’ guidelines regarding testing for CD

Condition Organizations recommending testing or considering

testing

ESPGHAN

(15)

ESsCD

(72)

NASPGHAN

(73)

NICE

(74)

ACG

(75)

WGO

(76)

1ST Degree Relatives Yes* Yes* Yes Yes Yes Yes

Type 1 Diabetes Yes* Yes* Yes Yes Yes

Autoimmune Thyroid Disease Yes* Yes Yes Yes Yes

Dental Enamel Defects Yes* Yes Yes Yes

Down Syndrome Yes* Yes Yes Yes Yes

Turner Syndrome Yes* Yes Yes Yes Yes

Irritable Bowel Syndrome** Yes Yes Yes

Short Stature / Poor Growth /

Failure to Thrive / Weight Loss

Yes* Yes* Yes Yes Yes Yes

IgA- Deficiency Yes* Yes* Yes Yes

Abnormal Liver Chemistry Yes* Yes Yes Yes Yes Yes

Chronic Fatigue Yes* Yes Yes Yes

Delayed Puberty / Amenorrhea Yes* Yes Yes Yes

ESPGHAN: European Society for Paediatric Gastroenterology, Hepatology and Nutrition, ESsCD: European Society

for the Study of Coeliac Disease, NASPGHAN: North American Society for Pediatric Gastroenterology, Hepatology

and Nutrition, NICE: National Institute for Health and Care Excellence, ACG: American College of Gastroenterology,

WGO: World Gastroenterology Organisation. *Recommendation only in children. **Most guidelines recommend

testing for symptoms overlapping with IBS.

25

Economical Aspects

Any public screening effort would demand resources, and a consideration of the potential

economic impact is therefore necessary. A study of primary care costs of CD in the UK found

increased health care costs for patients with CD compared to the general population, estimating

an increased annual cost of 91 GBP in the time leading up to, and 310 GBP after the diagnosis

was made (77). Costs before diagnosis included diagnostic procedures, which could potentially

become cheaper if serology plays a more central role. Costs after diagnosis was driven by

increased prescription (77). Although there are added costs in relation to CD, there is also added

costs to undiagnosed individuals with CD (78). A recent systematic review of the economic

burden of CD found that after starting a gluten free diet, CD patients attended school or work

more frequently, used less medication and visited their primary care physician less often than

before treatment. The authors concluded that at least in symptomatic patients, methods to

diagnose CD are cost-effective in North America and Europe (78).

Cost of long term treatment of CD is mainly related to the added cost of a gluten free diet. To

help with this extra financial burden patients in Norway receive a financial support of 1047

NOK per month (as of 01.01.2021) for individuals age 5-30 and 686 NOK for all others (79,

80). This number is based on a report by Forbruksforskningsinstituttet SIFO done in 2018 where

they estimated the extra cost of a gluten free diet for individuals aged 18-30 to be 655 NOK per

month (81). This financial support should ease the compliance to the gluten free diet, especially

for patients with lesser economical means. Any increase in the diagnostic rate of CD would

necessarily increase governmental costs to cover lifelong gluten free diets for the new patients.

Costs related to CD are not purely dietary however, they could also be related to poorer health

as a result of the disease. For instance in an American study, the annual cost of living with CD

in Olmstead County was estimated to be 5457 USD before diagnosis, which was reduced to

3339 USD after diagnosis (3), indicating an economical incentive for CD patients in general to

get diagnosed sooner rather than later. As health expenditure at the individual level is quite

different in the USA compared to Norway, more of these savings would presumably fall to the

government in Norway.

26

Ethical Considerations

Socioeconomic Differences

Traditionally there has been differences in help seeking behaviour among different

socioeconomic groups in Norway (82). There has however been a shift along with the primary

care shift to each patient being assigned their own general practitioner where the differences in

health utilization has diminished in primary care, albeit not in specialist outpatient clinics yet

(82). This has implications for a scenario in which CD screening is primary care driven. Given

the similar use of services already today, one would think that a screening programme would

uncover undiagnosed CD patients across all of the socioeconomic spectrum. As Norway has

large and increasing social inequalities in health, also when seen in a European perspective (83),

screening of CD could potentially help combat health inequalities in the population.

Quality of Life

An important measure of whether diagnosing CD is a worthwhile endeavour is the diagnosis’

impact on patients’ quality of life. In symptomatic patients, quality of life increases markedly

upon diagnosis and commencement of a gluten free diet (34). When it comes to asymptomatic

individuals diagnosed through screening however, the picture is less clear, with some concerns

that the added restrictiveness and laboriousness of a gluten free diet could do more harm than

the potentially minor negative effects that an unnoticed disease might have had (34). In general

there is a relative lack of knowledge regarding the natural course of asymptomatic CD if left

untreated (72).

Still, we do have some data on patients’ lives after getting a diagnosis of CD through screening.

A now somewhat older study from Italy showed a lower level compliance to a gluten free diet

in screening detected, compared to clinically detected, adolescents (84), seemingly lessening

the value of a screening detected diagnosis. Newer data on the other hand, from a larger Finnish

study, showed good compliance among screening detected CD patients. The same Finnish study

also showed that treated screening detected CD patients had a similar Quality of Life to that of

treated symptomatic CD and non-CD controls, and substantially higher than that of untreated

CD patients (85). On the contrary a Swedish study found no difference in Health Related

Quality of Life between screening detected CD in children before their diagnosis compared to

non-CD controls, arguing that mass screening of children for CD could not be justified based

on these children suffering from a poor Health Related Quality of Life at the time of diagnosis

(86). Related to this a UK study showed that screening detected patients to a larger extent

regretted ever getting the diagnosis, with 27% preferring never to have been diagnosed, still the

27

majority, 73%, were pleased with being diagnosed (87). Then again in a more recent Finnish

study of CD screening in children the vast majority of parents (98%) and children (93%) were

satisfied with getting the diagnosis, and the children experienced improved health and parents

reduced concerns (88), making a strong argument for the possibility of substantial positive

effects of a screening program. Along the same lines a study of screening in Sweden did show

that screening for CD was very well perceived by adolescents and their parents (89). Although

results are varying across different countries, it seems reasonable to expect that any Norwegian

effort to establish a screening programme should be able to resemble the results of our

neighbouring countries given our similar infrastructure and health care systems.

Do No Harm

In addition to the laboriousness and restrictiveness of a gluten free diet, CD patients will live

with the constant worry of accidental gluten consumption. Imposing these burdens onto the

most asymptomatic individuals, could potentially lead to more harm than good, breaking with

the principle of non-maleficence at the core of medical ethics. If this were to be the end result

of screening for CD then it would defeat the purpose. Then again the abovementioned studies

of patients’ satisfaction with getting the diagnosis argues that this might be of lesser concern.

In a scenario of widespread screening for CD, there would inevitably be a large number of

healthy individuals undergoing diagnostic procedures. For the great majority, this would

involve a varying degree of inconvenience, pain and anxiety, without detecting any diagnosis

or cause any consequent beneficial changes to their daily lives. Although minor to most, the

combined impact of the inconvenience of this procedure, given the large numbers of individuals

affected, does have a negative effect on any value of a potential screening program. To outweigh

this nuisance posed on the many, the test would need to have substantial positive effects for the

relatively few individuals diagnosed and treated as a result of the test – i.e. a significant

improvement in the health of screening detected CD patients.

Beneficence

Of importance to CD screening is what, if any, positive impact a screening detected diagnosis

would have on the lives of the individuals diagnosed. Shedding light on this is a study of young

adults at a US Air Force around 1950. Investigators retrospectively analysed old serology

samples and coupled it with data on the patients in the following 45 years. They found that

undiagnosed CD increased all-cause mortality almost 4-fold (90). Although it could be argued

that diagnostic approaches are better today, and perhaps these individuals would have been

sufficiently affected by their disease to be detected if they were young adults today, the study

28

still illustrates that there seems to be a substantial harm to living with undiagnosed CD. Along

the same lines a study from Finland showed that at-risk screening identified CD patients had

similar severity of symptoms to those with clinically detected CD (91), supporting identifying

CD through such screening.

Fair Use of Resources

From an ethical point of view the principle of justice comes into question when considering a

new screening approach. In Norway as of 2021 there is continuous political debate regarding

the workload of Norwegian primary care physicians, with average work weeks of 56 hours

reported (92). In a scenario where a serology based screening programme would have to be

implemented as a part of primary health care, the question stands whether this extra attention

to otherwise non-help seeking individuals would come at the cost of other patients more

deserving of medical attention. It could be that as it stands with primary care physicians a

limited resource, their participation in population wide screening could be an unfair use of

resources, risking an unintended and unjust impact on other patients.

DISCUSSION

If a more active case finding approach were to be applied to CD detection it could potentially

increase awareness among clinicians of the vagueness of symptoms and the ease of testing for

CD. However, active case finding would still be dependent on individuals actively seeking

medical attention, which could skew case finding towards only some groups of the population.

At-risk screening takes the help-seeking behaviour of the individual out of the equation with

presumably more objective criteria for testing. A combination of active case finding and at-risk

screening could yield good results. However, while it probably gets more positive results per

test compared to mass screening, it still leaves a big group undetected. Not to say that at-risk

screening could not be widened to include large parts of the general population.

In the end mass screening is the only option that would yield a near complete identification of

all CD patients at a given age. Number of repeat tests could be lowered if initial screening

included HLA-typing, as only genetically predisposed individuals would have to follow repeat

screenings. With HLA-typing costs presumably going down, different two-step approaches to

testing children could be increasingly more interesting. Although approaches such as the mass

wide HLA-typing followed by at-risk screening within HLA-DQ2 and HLA-DQ8-positive

individuals, does seem to have some merit, they do require testing of very many individuals

initially. Then again the Norwegian cohort mentioned above where this was done was mainly

aimed at T1DM research, which begs the question of whether HLA-screening of children could

29

impact case finding in several diseases at once, thereby becoming more doable in a “pay for 1

take 2” kind of deal.

Timing of any screening approach would have to be planned to identify as many as possible,

and at a time in life where diagnosis would lessen complications the most. If CD can debut at

any age, repeat screenings could potentially be done as a life-long project, this would however,

have to pass a tough cost-benefit analysis. Then again, if the data indicating that most patients

have onset of disease in early childhood is correct, it would make a potential screening program

more attractive, as screening adolescents would uncover the majority of patients, and repeat

screenings would not be necessary. In addition, screening for instance all 16 year olds would

allow for patient autonomy in a way screening toddlers would not. Still, as the age distribution

of disease onset is uncertain, the optimal age to maximize the diagnostic yield of any mass

screening remains uncertain. A screening programme would have to adapt to new knowledge

on this. Initially however, in a population not screened before, there could be a benefit to catch-

up screening of individuals past the age group mainly targeted by the screening programme.

Independently from how widely a potential screening strategy would be applied, there is still a

diagnostic challenge in the patients presenting with fluctuating serology or positive serology

combined with a normal duodenal mucosa (34). These patients would not qualify for the

diagnosis of CD, but would probably require further follow-ups and testing, perhaps gluten

challenges or diets. In line with what Wilson and Jungner outlined there would have to be a

clear plan for how to handle these borderline cases if a screening programme were to be

implemented in Norway. False positives does not however, seem to be a big problem in

screening studies of CD. Moreover, the quite recent developments making the serology only

approach sufficient in many children, has made screening for CD a more intriguing opportunity.

Another prerequisite that varies among countries is the availability of good treatment. This

would include good counselling and follow-up, and reasonably priced gluten free alternatives.

Although the framework for this is already in place in Norway, a rise in CD detection through

screening would necessarily imply an increase in demand of these services and increased

expenses in the national budget, something which would have to be prepared for.

When it comes to which individuals to screen, there seems to be wide support among guidelines

for something akin to at-risk screening, lesser so for population wide screening. First degree

relatives and T1DM patients are among the most promising at-risk screening groups. Also in

the case of known IgA deficiency or HLA predisposition there seems to be value in screening.

On the other hand comes conditions such as iron deficiency anaemia not responding to oral iron

30

therapy, one of the most common non-GI presentations of CD (73). It seems reasonable to

believe that these cases are among those already clinically diagnosed, meaning a superimposed

screening regimen would possibly add unnecessary bureaucracy without any added benefits. A

similar case could be made for the screening of CD in short stature in children as these children

would presumably be picked up by routine well child checks, and evaluated by doctors who

one would presume would have CD high on the list of differential diagnoses. This exemplifies

that a screening initiative is of most interest if it detects cases otherwise missed. One such

intriguing opportunity in Norway, is in children with dental enamel defects. As children

typically come to routine visits to the dentist (or dental hygienist) at 3, 5, 12, 15 and 18 years

of age (93). Time points which are different from other well child or routine follow up visits

with health professionals, thereby potentially giving dentists an opportunity to cover a window

in which the debut of CD might otherwise go unnoticed for quite some time.

Regarding the lack of institutions supporting population wide screening, though this seems to

be the natural initial stance, it is worth to remember the big differences seen across populations,

exemplified above with Japan as opposed to Europe. Thus, while international guidelines

typically serve a larger audience, Norwegian Health Services could reach different conclusions

when only concerned about the Norwegian population.

Speaking of potentially country specific concerns, the treatment offered to those who eventually

get the diagnosis comes with some challenges, despite the seeming simplicity. For instance

buying gluten free products adds an extra cost to daily living for coeliac patients, which could

potentially be a contributing factor to non-adherence in parts of the CD patient population. Then

again this extra cost is somewhat softened in Norway, with patients receiving monthly financial

support to cover extra expenses (79, 80). Moreover, for adolescents the pressure to fit in with

everyone else could also pose a challenge to diet adherence, and be a strain on the individual.

Furthermore, patients with CD face a daily fear of somehow ingesting trace amounts of gluten,

either accidentally in for instance restaurants or during travel. This constant pressure to be on

alert for gluten results in a high burden of disease, comparable to that of chronic diseases such

as diabetes (2).

Lastly, one of the major questions when it comes to screening for CD, is whether a gluten free

diet lowers the risk of malignancies. As discussed above there is an increased risk of certain

lymphomas in CD patients, and this risk is higher in patients not responding to a gluten free

diet. Together with other current research this suggests that a gluten free diet could be protective

against certain malignancies (94). Still, this has not been proven sufficiently, and given the

31

relatively low frequency of CD associated malignancies, this does not seem to justify wide

spread screening on account of lowering cancer risk.

Future Considerations

New Diagnostic Approaches

The abovementioned novel approach of diagnosing CD based on detecting gluten reactive T-

cells in blood instead of the traditional antibody based serology could potentially drastically

change diagnostic algorithms in CD. This could allow for the diagnosis of CD even in the

absence of a gluten containing diet, as these T-cells are present in plasma much longer than

TG2-autoantibodies (95), still without the need for an invasive biopsy. However, these tests are

currently at too high a cost to be effectively used in screening programmes (3), yet their non-

invasiveness seems promising. An even less invasive screening test than the blood samples

drawn for normal serology uses saliva to test for anti-TG2 autoantibodies. This inexpensive test

has shown promise in a large Italian screening study of children aged 6-8 years old (96). In

general any test that is cheaper, or otherwise better, would certainly contribute to lowering the

threshold for screening and testing.

Changing Prevalence

In recent years there have been signs of CD prevalence possibly increasing in Norway’s

paediatric population, seemingly not just an effect of increased diagnostic awareness (97). If

this is the case and the trend continues, then a scenario could develop where a substantially

larger subgroup of the population would benefit from screening. As the prevalence increases,

any increased diagnostic effort would certainly yield more results. In such a scenario the

question of CD screening would have to be revisited. Along the same lines epidemiologic data

giving more precise knowledge of the true age of onset of disease would help a give a more

targeted screening program.

Developing Therapeutics

New therapies are relevant to any discussion of screening for a disease, as they might change

the value of identifying new individuals. If treatment becomes easier, cheaper or more complete

this would add to the value of screening. Many potential therapies are being pursued in coeliac

disease research (72). This includes both symptomatic and curative pursuits such as

modification of dietary gluten, inhibition of the central TG2 enzyme, strengthening tight

junctions, blocking HLA molecules and developing immune tolerance through desensitization

32

(72). In the event of successful therapies replacing the gluten free diet, the pharmaceutical

industry could get an incentive to push increased rates of medicalization and thus increased

rates of diagnoses in CD.

Implementing a screening programme would take time, and by the time it is fully functional

there could be new approaches available that are preferable. In the meantime a screening

programme would however contribute to increased awareness among both health professionals

and the general public.

CONCLUSION

At the moment CD detection in Norway is based on the individual clinician suspecting it. The

disease is underdiagnosed in countries where this has been measured, making it a reasonable

assumption also in Norway. We know that in comparable countries to Norway there is

willingness among parents to have their children go through screening for CD, and a majority

of patients diagnosed through screening are satisfied with getting the diagnosis, yet it is not

clear to what extent their lives become better because of it. We still lack knowledge regarding

the natural course of disease in subclinical CD patients, which might be the biggest hurdle to

overcome for a screening programme to gain wide spread acceptance. The ease and

inexpensiveness at which it could be done however, through serological samples, especially in

at-risk groups, still seems to carry potential for a public health programme. Given the support

of the expert community to screen at-risk groups, and Norway being a country with the

necessary means to make it happen, it seems reasonable for public agencies to initiate

systematic screening programmes in at-risk groups such as first degree relatives and type 1

diabetes. Moreover, considering the impressive results of other comparable countries’

approaches to mass screening, and the not insignificant group of individuals otherwise missed

through combinations of active case finding and at-risk screening, mass screening of CD

seems promising. Thus, at least testing it out in Norway should be considered.

REFERENCES

1. Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-36.e2. 2. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391(10115):70-81. 3. Lundin KE, Wijmenga C. Coeliac disease and autoimmune disease-genetic overlap and screening. Nat Rev Gastroenterol Hepatol. 2015;12(9):507-15. 4. Mustalahti K, Catassi C, Reunanen A, Fabiani E, Heier M, McMillan S, et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann Med. 2010;42(8):587-95.

33

5. Kårhus LL, Thuesen BH, Skaaby T, Rumessen JJ, Linneberg A. The distribution of HLA DQ2 and DQ8 haplotypes and their association with health indicators in a general Danish population. United European Gastroenterol J. 2018;6(6):866-78. 6. Stamnaes J, Sollid LM. Celiac disease: Autoimmunity in response to food antigen. Semin Immunol. 2015;27(5):343-52. 7. Al-Toma A, Volta U, Auricchio R, Castillejo G, Sanders DS, Cellier C, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019;7(5):583-613. 8. Iversen R, Sollid LM. Autoimmunity provoked by foreign antigens. Science. 2020;368(6487):132-3. 9. Høydahl LS, Richter L, Frick R, Snir O, Gunnarsen KS, Landsverk OJB, et al. Plasma Cells Are the Most Abundant Gluten Peptide MHC-expressing Cells in Inflamed Intestinal Tissues From Patients With Celiac Disease. Gastroenterology. 2019;156(5):1428-39.e10. 10. Di Niro R, Mesin L, Zheng NY, Stamnaes J, Morrissey M, Lee JH, et al. High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med. 2012;18(3):441-5. 11. Di Niro R, Snir O, Kaukinen K, Yaari G, Lundin KE, Gupta NT, et al. Responsive population dynamics and wide seeding into the duodenal lamina propria of transglutaminase-2-specific plasma cells in celiac disease. Mucosal Immunol. 2016;9(1):254-64. 12. Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63(8):1210-28. 13. Gray AM, Papanicolas IN. Impact of symptoms on quality of life before and after diagnosis of coeliac disease: results from a UK population survey. BMC Health Services Research. 2010;10(1):105. 14. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-76; quiz 77. 15. Husby S, Koletzko S, Korponay-Szabó I, Kurppa K, Mearin ML, Ribes-Koninckx C, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. Journal of Pediatric Gastroenterology and Nutrition. 2020;70(1):141-56. 16. Popp A, Kivelä L, Fuchs V, Kurppa K. Diagnosing Celiac Disease: Towards Wide-Scale Screening and Serology-Based Criteria? Gastroenterol Res Pract. 2019;2019:2916024. 17. Penny HA, Raju SA, Lau MS, Marks LJ, Baggus EM, Bai JC, et al. Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts. Gut. 2020:gutjnl-2020-320913. 18. Christophersen A, Ráki M, Bergseng E, Lundin KE, Jahnsen J, Sollid LM, et al. Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge. United European Gastroenterol J. 2014;2(4):268-78. 19. Christophersen A, Risnes LF, Dahal-Koirala S, Sollid LM. Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond. Trends Mol Med. 2019;25(10):836-52. 20. Hære P, Høie O, Schulz T, Schönhardt I, Raki M, Lundin KE. Long-term mucosal recovery and healing in celiac disease is the rule - not the exception. Scand J Gastroenterol. 2016;51(12):1439-46. 21. Lebwohl B, Green PHR, Söderling J, Roelstraete B, Ludvigsson JF. Association Between Celiac Disease and Mortality Risk in a Swedish Population. Jama. 2020;323(13):1277-85. 22. van Gils T, Nijeboer P, Overbeek LI, Hauptmann M, Castelijn DA, Bouma G, et al. Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up:Celiac disease, lymphoma and GI carcinoma. United European Gastroenterology Journal. 2018;6(10):1485-95. 23. Lebwohl B, Granath F, Ekbom A, Smedby KE, Murray JA, Neugut AI, et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med. 2013;159(3):169-75.

34

24. Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, Absan H, et al. Characteristics of adult celiac disease in the USA: results of a national survey. The American Journal of Gastroenterology. 2001;96(1):126-31. 25. Størdal K, Kahrs C, Tapia G, Agardh D, Kurppa K, Stene LC. Review article: exposure to microbes and risk of coeliac disease. Alimentary Pharmacology & Therapeutics. 2021;53(1):43-62. 26. Choung RS, Khaleghi S, Cartee AK, Marietta EV, Larson JJ, King KS, et al. Community-Based Study of Celiac Disease Autoimmunity Progression in Adults. Gastroenterology. 2020;158(1):151-9.e3. 27. Andermann A, Blancquaert I, Beauchamp S, Déry V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ. 2008;86(4):317-9. 28. Wilson JMG, Jungner G. PRINCIPLES AND PRACTICE OF SCREENING FOR DISEASE. WHO Public Health Papers. 1968(34). 29. OUS. Nyfødtscreening [Web page]. https://oslo-universitetssykehus.no: Oslo universitetssykehus; 2020 [updated 2020 4 December; cited 2021 25 January]. Available from: https://oslo-universitetssykehus.no/avdelinger/barne-og-ungdomsklinikken/nyfodtscreeningen/nyfodtscreening. 30. Kreftregisteret. Livmorhalsprogrammet [Web page]. https://www.kreftregisteret.no: Kreftregisteret; 2020 [updated 2020 23 September; cited 2021 25 January]. Available from: https://www.kreftregisteret.no/screening/livmorhalsprogrammet/. 31. Zahl PH, Mæhlen J. Overdiagnosis of breast cancer after 14 years of mammography screening. Tidsskr Nor Laegeforen. 2012;132(4):414-7. 32. Kalager M. Primum non nocere. Tidsskr Nor Laegeforen. 2012;132(4). 33. Clark J. Medicalization of global health 1: has the global health agenda become too medicalized? Global Health Action. 2014;7(1):23998. 34. Kivelä L, Kurppa K. Screening for coeliac disease in children. Acta Paediatr. 2018;107(11):1879-87. 35. Alessandrini S, Giacomoni E, Muccioli F. Mass population screening for celiac disease in children: the experience in Republic of San Marino from 1993 to 2009. Italian Journal of Pediatrics. 2013;39(1):67. 36. Mäki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, et al. Prevalence of Celiac disease among children in Finland. N Engl J Med. 2003;348(25):2517-24. 37. Stahl MG, Geno Rasmussen C, Dong F, Waugh K, Norris JM, Baxter J, et al. Mass Screening for Celiac Disease: The Autoimmunity Screening for Kids Study. Am J Gastroenterol. 2020. 38. Almazán MV, Ortega E, Moreno Torres R, Tovar M, Romero J, López-Casado M, et al. Diagnostic screening for subclinical celiac disease using a rapid test in children aged 2-4. Pediatr Res. 2015;78(3):280-5. 39. De Silvestri A, Capittini C, Poddighe D, Valsecchi C, Marseglia G, Tagliacarne SC, et al. HLA-DQ genetics in children with celiac disease: a meta-analysis suggesting a two-step genetic screening procedure starting with HLA-DQ β chains. Pediatr Res. 2018;83(3):564-72. 40. Tapia G, Chudá K, Kahrs CR, Stene LC, Kramna L, Mårild K, et al. Parechovirus Infection in Early Childhood and Association With Subsequent Celiac Disease. Am J Gastroenterol. 2020. 41. Vriezinga SL, Auricchio R, Bravi E, Castillejo G, Chmielewska A, Crespo Escobar P, et al. Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med. 2014;371(14):1304-15. 42. Fukunaga M, Ishimura N, Abe T, Takeda M, Isomura M, Kinoshita Y, et al. Serological screening for celiac disease in adults in Japan: Shimane CoHRE study. JGH Open. 2020;4(4):558-60. 43. Horwitz A, Skaaby T, Kårhus LL, Schwarz P, Jørgensen T, Rumessen JJ, et al. Screening for celiac disease in Danish adults. Scand J Gastroenterol. 2015;50(7):824-31. 44. Kårhus LL, Thuesen BH, Rumessen JJ, Linneberg A. Symptoms and biomarkers associated with celiac disease: evaluation of a population-based screening program in adults. Eur J Gastroenterol Hepatol. 2016;28(11):1298-304.

35

45. Hjelle AM, Apalset E, Mielnik P, Nilsen RM, Lundin KEA, Tell GS. Positive IgA against transglutaminase 2 in patients with distal radius and ankle fractures compared to community-based controls. Scand J Gastroenterol. 2018;53(10-11):1212-6. 46. Cerutti F, Bruno G, Chiarelli F, Lorini R, Meschi F, Sacchetti C. Younger Age at Onset and Sex Predict Celiac Disease in Children and Adolescents With Type 1 Diabetes. An Italian multicenter study. 2004;27(6):1294-8. 47. Larsson K, Carlsson A, Cederwall E, Jönsson B, Neiderud J, Jonsson B, et al. Annual screening detects celiac disease in children with type 1 diabetes. Pediatric Diabetes. 2008;9(4pt2):354-9. 48. Kumral D, Syed S. Celiac Disease Screening for High-Risk Groups: Are We Doing It Right? Dig Dis Sci. 2020;65(8):2187-95. 49. Leeds JS, Hopper AD, Hadjivassiliou M, Tesfaye S, Sanders DS. High Prevalence of Microvascular Complications in Adults With Type 1 Diabetes and Newly Diagnosed Celiac Disease. Diabetes Care. 2011;34(10):2158-63. 50. Ch'ng CL, Biswas M, Benton A, Jones MK, Kingham JG. Prospective screening for coeliac disease in patients with Graves' hyperthyroidism using anti-gliadin and tissue transglutaminase antibodies. Clin Endocrinol (Oxf). 2005;62(3):303-6. 51. Teixeira LM, Nisihara R, Utiyama SR, Bem RS, Marcatto C, Bertolazo M, et al. Screening of celiac disease in patients with autoimmune thyroid disease from Southern Brazil. Arq Bras Endocrinol Metabol. 2014;58(6):625-9. 52. Odineal DD, Gershwin ME. The Epidemiology and Clinical Manifestations of Autoimmunity in Selective IgA Deficiency. Clin Rev Allergy Immunol. 2020;58(1):107-33. 53. Ludvigsson JF, Neovius M, Hammarström L. Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study. J Clin Immunol. 2014;34(4):444-51. 54. Liu E, Wolter-Warmerdam K, Marmolejo J, Daniels D, Prince G, Hickey F. Routine Screening for Celiac Disease in Children With Down Syndrome Improves Case Finding. J Pediatr Gastroenterol Nutr. 2020;71(2):252-6. 55. Mårild K, Stephansson O, Grahnquist L, Cnattingius S, Söderman G, Ludvigsson JF. Down Syndrome Is Associated with Elevated Risk of Celiac Disease: A Nationwide Case-Control Study. The Journal of Pediatrics. 2013;163(1):237-42. 56. Swigonski NL, Kuhlenschmidt HL, Bull MJ, Corkins MR, Downs SM. Screening for Celiac Disease in Asymptomatic Children With Down Syndrome: Cost-effectiveness of Preventing Lymphoma. Pediatrics. 2006;118(2):594-602. 57. Mårild K, Størdal K, Hagman A, Ludvigsson JF. Turner Syndrome and Celiac Disease: A Case-Control Study. Pediatrics. 2016;137(2):e20152232. 58. Skodje GI, Sarna VK, Minelle IH, Rolfsen KL, Muir JG, Gibson PR, et al. Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity. Gastroenterology. 2018;154(3):529-39.e2. 59. Ford AC, Chey WD, Talley NJ, Malhotra A, Spiegel BMR, Moayyedi P. Yield of Diagnostic Tests for Celiac Disease in Individuals With Symptoms Suggestive of Irritable Bowel Syndrome: Systematic Review and Meta-analysis. Archives of Internal Medicine. 2009;169(7):651-8. 60. Smalley W, Falck-Ytter C, Carrasco-Labra A, Wani S, Lytvyn L, Falck-Ytter Y. AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D). Gastroenterology. 2019;157(3):851-4. 61. Mahadev S, Laszkowska M, Sundström J, Björkholm M, Lebwohl B, Green PHR, et al. Prevalence of Celiac Disease in Patients With Iron Deficiency Anemia—A Systematic Review With Meta-analysis. Gastroenterology. 2018;155(2):374-82.e1. 62. El-Hodhod MA, El-Agouza IA, Abdel-Al H, Kabil NS, Bayomi KA. Screening for celiac disease in children with dental enamel defects. ISRN Pediatr. 2012;2012:763783. 63. Basso MS, Zanna V, Panetta F, Caramadre AM, Ferretti F, Ottino S, et al. Is the screening for celiac disease useful in anorexia nervosa? Eur J Pediatr. 2013;172(2):261-3.

36

64. Saldanha NE, Weiselberg EC, Fisher M. Screening for celiac disease in patients with eating disorders. Int J Adolesc Med Health. 2016;30(1). 65. Nenna R, Mosca A, Mennini M, Papa RE, Petrarca L, Mercurio R, et al. Coeliac disease screening among a large cohort of overweight/obese children. J Pediatr Gastroenterol Nutr. 2015;60(3):405-7. 66. Calcaterra V, Regalbuto C, Manuelli M, Klersy C, Pelizzo G, Albertini R, et al. Screening for celiac disease among children with overweight and obesity: toward exploring celiac iceberg. J Pediatr Endocrinol Metab. 2020. 67. Calderoni S, Santocchi E, Del Bianco T, Brunori E, Caponi L, Paolicchi A, et al. Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder. Ital J Pediatr. 2016;42(1):98. 68. Collin P, Syrjänen J, Partanen J, Pasternack A, Kaukinen K, Mustonen J. Celiac disease and HLA DQ in patients with IgA nephropathy. Am J Gastroenterol. 2002;97(10):2572-6. 69. Sahin I, Eminbeyli L, Andic S, Tuncer I, Koz S. Screening for celiac disease among patients with chronic kidney disease. Ren Fail. 2012;34(5):545-9. 70. Ahmad F, Alam S, Shukla I, Sherwani R, Ali SM. Screening children with severe short stature for celiac disease using tissue transglutaminase. Indian J Pediatr. 2010;77(4):387-90. 71. Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63(8):1210-28. 72. Al-Toma A, Volta U, Auricchio R, Castillejo G, Sanders DS, Cellier C, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterology Journal. 2019;7(5):583-613. 73. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guideline for the Diagnosis and Treatment of Celiac Disease in Children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology and Nutrition. 2005;40(1):1-19. 74. NICE. Coeliac disease: recognition, assessment and management [Guideline]. https://www.nice.org.uk: NICE; 2015 [updated 2015 2 September; cited 2021 25 January]. Available from: https://www.nice.org.uk/guidance/ng20/resources/coeliac-disease-recognition-assessment-and-management-pdf-1837325178565. 75. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Official journal of the American College of Gastroenterology | ACG. 2013;108(5):656-76. 76. WGO. World Gastroenterology Organisation Global Guidelines Celiac disease [Guideline]. http://staging.worldgastroenterology.org: World Gastroenterology Organizaton; 2016 [updated 2016 July; cited 2021 25 January]. Available from: http://staging.worldgastroenterology.org/guidelines/global-guidelines/celiac-disease/celiac-disease-english. 77. Violato M, Gray A, Papanicolas I, Ouellet M. Resource use and costs associated with coeliac disease before and after diagnosis in 3,646 cases: results of a UK primary care database analysis. PLoS One. 2012;7(7):e41308. 78. Mearns ES, Taylor A, Boulanger T, Craig KJ, Gerber M, Leffler DA, et al. Systematic Literature Review of the Economic Burden of Celiac Disease. Pharmacoeconomics. 2019;37(1):45-61. 79. Nav. Grunnstønad [Goverment document]. https://www.nav.no: Nav; 2006 [updated 2020 3 December; cited 2021 25 January]. Available from: https://www.nav.no/no/person/familie/grunn-og-hjelpestonad/grunnstonad. 80. Nav. Grunn- og hjelpestønad [Government document]. https://www.nav.no: Nav; 2014 [updated 2020 21 December; cited 2021 25 January]. Available from: https://www.nav.no/no/nav-og-samfunn/kontakt-nav/oversikt-over-satser/grunn-og-hjelpestonad. 81. Roos G, Laitala K, Klepp IG, Austgulen MH, Borgeraas E. Kartlegging av ekstrautgifter. Utgifter til mat for personer med cøliaki og andre diagnosegrupper og til klær og sko for personer med

37

sykdommer eller lidelser som fører til ekstraordinær slitasje på klær eller sengetøy. Oslo: Forbruksforskningsinstituttet SIFO; 2018. 82. Vikum E, Bjørngaard JH, Westin S, Krokstad S. Socio-economic inequalities in Norwegian health care utilization over 3 decades: the HUNT Study. European Journal of Public Health. 2013;23(6):1003-10. 83. Strand BH, Madsen C. Social inequalities in health [Public Health Report]. https://www.fhi.no: Norwegian Institute of Public Health; 2016 [updated 2018 15 October; cited 2021 25 January]. Available from: https://www.fhi.no/en/op/hin/groups/social-inequalities/. 84. Fabiani E, Taccari LM, Rätsch I-M, Di Giuseppe S, Valentino Coppa G, Catassi C. Compliance with gluten-free diet in adolescents with screening-detected celiac disease: A 5-year follow-up study. The Journal of Pediatrics. 2000;136(6):841-3. 85. Viljamaa M, Collin P, Huhtala H, Sievänen H, Mäki M, Kaukinen K. Is coeliac disease screening in risk groups justified? A fourteen-year follow-up with special focus on compliance and quality of life. Aliment Pharmacol Ther. 2005;22(4):317-24. 86. Nordyke K, Norström F, Lindholm L, Carlsson A, Danielsson L, Emmelin M, et al. Health-related quality-of-life in children with coeliac disease, measured prior to receiving their diagnosis through screening. Journal of Medical Screening. 2011;18(4):187-92. 87. Whitaker JK, West J, Holmes GK, Logan RF. Patient perceptions of the burden of coeliac disease and its treatment in the UK. Aliment Pharmacol Ther. 2009;29(10):1131-6. 88. Kinos S, Kurppa K, Ukkola A, Collin P, Lähdeaho ML, Huhtala H, et al. Burden of illness in screen-detected children with celiac disease and their families. J Pediatr Gastroenterol Nutr. 2012;55(4):412-6. 89. Rosén A, Emmelin M, Carlsson A, Hammarroth S, Karlsson E, Ivarsson A. Mass screening for celiac disease from the perspective of newly diagnosed adolescents and their parents: a mixed-method study. BMC Public Health. 2011;11:822. 90. Rubio–Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann F, et al. Increased Prevalence and Mortality in Undiagnosed Celiac Disease. Gastroenterology. 2009;137(1):88-93. 91. Kivelä L, Kaukinen K, Huhtala H, Lähdeaho M-L, Mäki M, Kurppa K. At-Risk Screened Children with Celiac Disease are Comparable in Disease Severity and Dietary Adherence to Those Found because of Clinical Suspicion: A Large Cohort Study. The Journal of Pediatrics. 2017;183:115-21.e2. 92. Rebnord IK, Eikeland OJ, Hunskår S, Morken T. Fastlegers tidsbruk. Bergen: Nasjonalt kompetansesenter for legevaktmedisin; 2018. 93. Helsedirektoratet. Tann- og munnundersøkelser av barn og unge [Guideline]. https://www.helsedirektoratet.no: Helsedirektoratet; 2019 [updated 2019 29 January; cited 2021 25 January]. Available from: https://www.helsedirektoratet.no/retningslinjer/tannhelsetjenester-til-barn-og-unge-020-ar/tann-og-munnundersokelser-av-barn-og-unge?fbclid=IwAR26Axmjj5EXe3Eg3BB0zyTc8qpgZdm_uyA-pa2cCpFjuhKjQkdrVkJBUU0#barn-og-unge-320-ar-bor-fa-en-statusundersokelse-ved-bestemte-aldre. 94. Ludvigsson JF, Card TR, Kaukinen K, Bai J, Zingone F, Sanders DS, et al. Screening for celiac disease in the general population and in high-risk groups. United European Gastroenterol J. 2015;3(2):106-20. 95. Risnes LF, Christophersen A, Dahal-Koirala S, Neumann RS, Sandve GK, Sarna VK, et al. Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease. J Clin Invest. 2018;128(6):2642-50. 96. Bonamico M, Nenna R, Montuori M, Luparia RP, Turchetti A, Mennini M, et al. First salivary screening of celiac disease by detection of anti-transglutaminase autoantibody radioimmunoassay in 5000 Italian primary schoolchildren. J Pediatr Gastroenterol Nutr. 2011;52(1):17-20. 97. Beitnes AR, Vikskjold FB, Jóhannesdóttir GB, Perminow G, Olbjørn C, Andersen SN, et al. Symptoms and Mucosal Changes Stable During Rapid Increase of Pediatric Celiac Disease in Norway. J Pediatr Gastroenterol Nutr. 2017;64(4):586-91.