Screening for celiac disease in the general population and in high-risk groups

Prevalence of CD: “That the disease is common and well defined”

In much of the Western world, CD affects about 1% of the population, but the prevalence varies between countries (e.g. 0.3% in Germany,³ 0.7% in Italy,³ 0.7–0.8% in the US^16,17 and 1.8% in Sweden²). There are reports of even higher prevalence in certain calendar- and age-specific population-strata in Sweden.¹⁸

The proportion of individuals with CD whom have received a physician-assigned diagnosis of CD also varies (e.g. 25% in Finland and 6% in Italy),³ probably reflecting the general awareness of CD in each country. The ratio between diagnosed and undiagnosed CD has implications for screening, because with a large proportion of undiagnosed CD, the arguments for screening become stronger. Despite the slightly varying prevalence of CD, it is one of the most common lifelong diseases in any Western country (especially in children). While the prevalence of CD may be lower in some non-Western countries,^19,20 there are also reports of extremely high prevalences in others.²¹ We concluded that this WHO condition is fulfilled.

There is currently an ongoing debate on how to define CD. Our research group recently published a paper on the definitions of CD, where CD was defined as “a chronic, small intestinal immune-mediated enteropathy, precipitated by exposure to dietary gluten in genetically-predisposed individuals.”¹⁵ The related non-celiac gluten sentivitity^15,22,23 was defined as: “one or more of a variety of immunological, morphological or symptomatic manifestations that are precipitated by the ingestion of gluten in people in whom CD has been excluded.”¹⁵ The definition of CD has important implications for CD screening, because so far, most research on complications and QOL have been performed in individuals with biopsy-verified CD, and that data cannot automatically be extrapolated to non-celiac gluten sensitivity. The risk of complications may also vary with the underlying histopathology in CD.²⁴

Serology sensitivity and specificity: “That screening tests are simple, safe and accurate”

The WHO stipulates that for mass screening to be an option, screening tests with high sensitivity, specificity,²⁵ positive predictive value (PPV) and negative predictive value (NPV) must be available. For any of the available tests, a most important aspect is that the testing should be carried out when the patient is on a gluten-containing diet. It is, therefore, of crucial importance that the patient remains on a normal diet throughout the investigation for CD, and our discussion assumes this will be so.

So-called antigliadin antibodies used in the 1980s and 1990s have low PPV, even in high-risk groups; and therefore, they have largely been replaced by the more specific endomysium (EMA) and tissue transglutaminase antibodies (TTG). The introduction of endomysium antibodies was initially promising, because their sensitivity and specificity seemed to be at least 90–95%; but over time, issues regarding inter-observer reliance/interpretability and cost, have limited its use as the first-line screening tool for CD. Though TTG antibodies can also be elevated in non-CD diseases such as liver disease,²⁶ gastrointestinal infections²⁷ and certain heart diseases;^28,29 TTG, like EMA, offers high sensitivity and specificity.³⁰

One further test recently gained some popularity: This is for deamidated gliadin peptide antibodies (DGP); however, one meta-analysis found that TTG performs better than DGP.³¹ TTG is therefore often used for screening of high-risk groups, but it has also been used in large-scale screening projects of the general population, including that of a multi-national European study encompassing more than 29,000 individuals.³ In this European multi-center study, 75% (n = 292/391) of individuals with positive TTG were positive for EMA, but only 2.6% of those had borderline TTG values (n = 10/384).³ In the 147 individuals with both positive EMA and positive/borderline TTG, 100 had an enteropathy that was typical of CD, equaling 68%.³ When Hopper et al.³² screened a population of 2000 individuals undergoing endoscopy for various indications, the PPV for CD (as defined by villous atrophy) in TTG+ individuals was 28–29%; but with a much higher figure reported in a general population study by Katz et al.,³³ as well as by Sugai et al.³⁴ Even a PPV of around 30% compares favorably with the PPV of guaiac fecal occult blood (FOB) testing for colorectal cancer (a test already accepted for screening in a number of countries), for example; however, in the case of FOB screening, confirmatory testing is recommended (in the case of CD in adults, through a small intestinal biopsy).¹⁴

One further aspect to consider in the use of TTG is that when determining TTG (TG2 antibodies) by enzyme-linked immunosorbent assay (ELISA), it is important to bear in mind that the performance of commercial ELISA TTG assays may vary depending on the quality of the TTG antigen.³⁵ The method of extraction, the purity of TTG and the production and processing of recombinant antigen may all have an effect on the test results.^35–37 Furthermore, as TTG can exist in two divergent conformations (open extended or closed), dependent on the activity of the enzyme,³⁸ this also will influence the performance of the assay, with the open TTG being the superior antigen.³⁹ For the above-mentioned reasons, the different commercial TTG-ELISA tests can yield differing numbers of false-negative or false-positive results. Sequential strategies may also be used, to increase the PPV.^2,40

Screening is culturally acceptable

A third WHO criterion is that “a screening test should be culturally acceptable.” There are areas in the world⁴² where blood testing may not be culturally acceptable, but in the majority of countries (including those where earlier research shows a high prevalence of CD), blood testing is culturally accepted.

The GFD: “That a treatment is available.”

This condition is clearly fulfilled in CD. Use of a GFD is an effective treatment for CD; and in symptomatic patients, the benefits of dietary treatment are well established, as it has been shown to decrease clinical symptoms, as well as to reduce the excess risk of complications.^43–45

Nevertheless, the advantages of dietary treatment in screening-detected but apparently asymptomatic individuals remain doubtful, and it is by no means settled that a GFD results in similar health gains;^46–51 however, it is important to note that many screening-detected CD patients are not truly asymptomatic at diagnosis; and may, once on a GFD, recognize that they had suffered from CD-related symptoms before the diagnosis. It is suggested that many undiagnosed celiac patients accept a state of chronic vague ill health as a normal condition, but are able to recognize this only after they have been placed on a GFD.^47,52–54

A recent randomized study also shows that apparently asymptomatic EMA-positive subjects seem to benefit from their serological screening and subsequent GFD,⁵⁵ thereby supporting earlier evidence from Dickey et al.;⁵⁶ however, some authors have suggested that EMA positivity in individuals with normal mucosa constitutes a separate entity (potential CD), different from CD.⁵⁷

A strict GFD sets major limitations on daily life and it is expensive and difficult to maintain.^58,59 Furthermore, removal of gluten from baked products makes them less palatable than comparable products in the normal diet. Due to these unpleasant aspects, adherence to a GFD often remains inadequate.⁶⁰ Individuals who are found through screening programs to have CD may feel themselves healthy and they do not expect to gain health on a treatment similar to those who were detected due to having symptoms. Consequently, screening-detected subjects may be even less willing to adhere to a strict GFD.^53,61,62 The possible non-adherence to a GFD is an essential issue, when weighing the harms and benefits of CD screening; as a low rate of adherence would abolish any advantages of performing that screening. It is important in this regard to recognize that good dietary adherence can be achieved in screening-detected CD patients (adherence rates of 85% in the symptom-detected CD patients and 79–91% in the screening-detected ones),^53,63 even after long-term treatment;^52,64 however, there is evidence to suggest that dietary lapses could be more common in the initially asymptomatic screening-detected patients than in the symptomatic ones.⁵³ Furthermore, patients suffering from Type 1 diabetes mellitus and found to have CD by risk-group screening may evince lower dietary adherence rates than are reported in screening studies in general (40–63%).^65–67

When prescribing a GFD to a healthy screening-detected patient, one should remember that a GFD is not nutritionally optimal and may have adverse consequences. GFD may potentially expose individuals to high sugar, and low fiber and mineral intake;^68,69 which might cause different long-term negative health consequences, such as constipation.⁷⁰ In addition, there is concern that patients might gain undesirable weight while on a GFD.^71,72 Altogether, it would thus be essential to evaluate the consequences of GFD treatment before any screening programs for the disease are instituted.

Diagnostic delay: “That clinical detection is difficult”

Typically, CD is characterized by diarrhea, malabsorption and failure to thrive in childhood, although during the last 2 decades, the age of diagnosis has shifted upward and many patients exhibit only minor symptoms.^73–75 Due to the inconsistency of their symptoms, a substantial proportion of celiac patients have a previous diagnosis of irritable bowel syndrome (IBS).^76,77 Unfortunately, these symptoms do not predict CD in general population studies.^2,33,78,79 Furthermore, increasing numbers of CD patients are diagnosed because of extraintestinal symptoms or by screening of at-risk groups.^73,74 Probably due to the vague nature of presenting symptoms, the delay from first symptoms to CD diagnosis has been reported to be unacceptably long, at between 5–10 years for many persons;^73,80–85 and so the need for earlier diagnosis, even by mass screening, has been advocated.

Untreated disease leads to complications: “That if undiagnosed and untreated, the disease will lead to severe complications”

The WHO stipulates that prevention of complications shall follow upon disease detection, if mass screening is implemented. This statement is conditional on two facts:

• That undiagnosed disease confers complications; and
• That these complications can be prevented by a treatment; in this case, a GFD.

Given the importance of genetic factors in the etiology of CD, it may be assumed that comorbidity linked to underlying shared risk factors cannot be modified by diagnosing CD and introducing a GFD.

It seems clear that the majority of gastrointestinal symptoms in CD are alleviated after the introduction of a GFD, but the evidence is less clear about whether most complications are influenced by a GFD. Weaknesses of previous research in this area include: lack of strict evaluation of GFD, low study power, short follow-up, a difficulty in disentangling the effects of age at diagnosis and the duration of gluten exposure that will likely both be linked to early diagnosis.

It should be noted that duration of CD is not equal to diagnostic delay. In the recent ‘Proconsul’ study, complications in CD were associated with a short diagnostic delay,⁸⁶ but it cannot be ruled out that earlier celiac diagnosis was prompted by the symptoms and signs from the celiac complication.

QOL aspects of screening for CD

In symptomatic CD, the GFD results in rapid recovery from symptoms, paralleled with improvement in QOL^{46,53,125–127} (Table 2); however, screening-detected CD patients may have considered themselves healthy before the diagnosis, and now the stigma of a chronic disorder¹²⁸ and need of major dietary restrictions may potentially even increase their self-perceived burden of illness and impair their QOL.^129–131

Prospective studies on QOL in CD patients detected by screening of at-risk groups or in populations in general are limited (Table 2). According to these studies, QOL in screening-detected CD patients at or before diagnosis, especially in those whom are asymptomatic, is often similar to^{46,50,53,125,126} or lower^47,52,53 than that found in control populations. In screening-detected patients, GFD treatment does not necessarily result in improvement of QOL,^46,53,126 but some studies imply that the diet may also have a positive impact on the health and well-being of these patients.^47,52,53,125 Still, data suggest that screening-detected patients without symptoms may experience the diagnosis of CD more negatively than the patients with symptoms.^48,53 This would suggest that early detection of CD by mass screening in a healthy adult population would not unequivocally result in a self-perceived health gain. Furthermore, data on long-term treatment in screening-detected patients is scarce.^52,64 These issues call for comprehensive studies before implementation of large-scale CD screening programs.

Cost-benefit of screening: “That testing and treatment is cost-effective”

As has been outlined above, the likely benefit or even the potential harm to undetected coeliac patients from screening detection is as yet poorly defined. In addition, symptomatic undiagnosed CD and diagnosed CD are both likely to confer increased costs to the individual patient and to society, but these costs are shared differently in different countries. Determining whether screening and detection of asymptomatic CD will lead to health gains at an acceptable cost, or even to economic benefits, is therefore extremely difficult; however, a number of studies have been conducted in this area. Some of these consider only the costs of detecting a new case by varying screening strategies, or apply only to specific high-risk groups, and there are very few that have attempted to model both costs and health benefits, to determine the cost of gaining a quality-adjusted life year (QALY). Only three of these refer to general population screening.

In a UK context, perhaps the most influential of these papers to date is the Health Technology Assessment (HTA) sponsored study, by Dretzke et al.¹³² (the only such study that is considered in the development of the current UK national guidelines; and one that is specifically looking at newly-diagnosed Type I diabetic children). This study finds that serological testing, followed by confirmatory biopsy and then treatment with GFD, provides additional QALYs at an incremental cost of between £12,250 and £20,160, when performed in children with newly-diagnosed Type 1 diabetes. To derive these estimates, the authors assumed, among other things, that untreated asymptomatic CD would cause the loss of 4 years of life, and reduce QOL from the 88% optimal assumed baseline for treated disease, to 82% of optimal.

Another prominent analysis by Hershcovici et al.¹³³ examines the cost-effectiveness of mass screening. This paper found that the cost for each QALY gained through mass CD screening is about US$49,000 (Table 3);¹³³ however, it is important to note that this cost, and the conclusion that mass screening in young adults is cost-effective, is again based on a number of assumptions. The authors of the Hershcovici et al.¹³³ paper assume that the standardized mortality ratio (SMR) is 1.6 in patients with symptoms that are ‘undiagnosed CD’, and 1.1 in ‘diagnosed’ patients on a GFD; however, most studies on mortality in diagnosed CD find relative risks of deaths of around 1.3–1.4^8,104 (and in a Swedish study,⁸ it was estimated that 83% of patients adhere to their diet). Hence, with a smaller gap between the mortality risk estimates between diagnosed and undiagnosed celiac patients, mass screening may not be cost-effective. This is well illustrated by the study by Shamir et al.¹³⁴ (Table 3), which though finding on an assumption of a SMR of 1.6 for undetected disease that screening is cost effective, shows in a sensitivity analysis that if the SMR fell to 1.3, then the cost per QALY rises to over US$100,000.

Cost-effectiveness analyses are also dependent on the degree of adherence to a GFD, and where Hershcovici et al.¹³³ assume a dietary adherence of 80% in patients with symptomatic CD, others find the lowest dietary adherence in screening-detected asymptomatic patients.⁴⁹ Finally, cost-effectiveness is dependent on the duration of symptoms before diagnosis. Hershcovici et al.¹³³ report that mass screening would be effective, if the diagnostic delay was 6 years or more. With increased awareness of CD, the diagnostic delay is likely to decrease. At present, some studies suggest that the delay is ≥ 6 years,^80,85 but others suggest that it is less (4.9 years).¹³⁵

Finally, Park et al.¹³⁶ recently compared two different strategies to prevent bone loss and fractures in patients with undiagnosed or subclinical CD. Their study found that symptomatic at-risk screening was more cost-effective than universal serological screening. Though again, the assumptions of their base model can be challenged, they find that screening of symptomatic and high-risk subjects is the dominant strategy, when compared to universal screening, producing greater QOL gains at a lower cost. Furthermore, this strategy remains the more cost-effective option when testing the sensitivity of the model to variation in their assumptions.

We conclude that more data on the cost-effectiveness of mass screening for CD in the general population is needed.