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The prevalence of celiac disease in Europe: Results of a centralized, international mass screening project

The prevalence of celiac disease in Europe: Results of a centralized, international mass... Introduction. Although the prevalence of celiac disease (CD) has been extensively investigated in recent years, an accurate estimate of CD frequency in the European population is still lacking. The aims of this study were: 1) to establish accurately the prevalence of CD in a large sample of the European population (Finland, Germany, Italy, and UK), including both children and adults; and 2) to investigate whether the prevalence of CD signifi cantly varies between different areas of the European continent. Materials and methods. Samples were drawn from the four populations. All 29,212 participants were tested for CD by tissue transglutaminase (tTG) antibody test. Positive and border-line fi ndings were further tested for serum endomysial antibodies (EMA). All serological determinations were centrally performed. Small-bowel biopsies were recommended to autoantibody- positive individuals. Previously diagnosed cases were identifi ed. Results. The overall CD prevalence (previously diagnosed plus anti-tTG and EMA positives) was 1.0% (95% CI 0.9 – 1.1). In subjects aged 30 – 64 years CD prevalence was 2.4% in Finland (2.0 – 2.8), 0.3% in Germany (0.1 – 0.4), and 0.7% in Italy (0.4 – 1.0). Sixty-eight percent of antibody-positive individuals showed small-bowel mucosal changes typical for CD (Marsh II/III lesion). Conclusions. CD is common in Europe. CD prevalence shows large unexplained differences in adult age across different European countries. Key words: Anti-transglutaminase antibodies , celiac disease , epidemiology , population-based screening , prevalence be even totally absent despite the presence of the Introduction mucosal lesion. Patients may be clinically silent Celiac disease (CD) is an autoimmune disorder for years or decades or present only extraintestinal triggered by gluten, the major protein complex found complications, such as osteoporosis, dental enamel in wheat, barley, and rye, in genetically predisposed defects, or peripheral or central nervous system individuals (1). The major problem in diagnosing the involvement (2). disease is its multifaceted clinical picture. Gastroin- Serum IgA class tissue transglutaminase (tTG) testinal symptoms may vary from mild to severe or antibody enzyme-linked immunosorbent assay Correspondence: Professor Carlo Catassi, Department of Pediatrics, Università Politecnica delle Marche, Via Corridoni 11, 60123 Ancona, Italy. Fax: +39 071 36281. E-mail: [email protected] (Received 10 March 2009; accepted 30 June 2010) ISSN 0785-3890 print/ISSN 1365-2060 online © 2010 Informa UK Ltd. DOI: 10.3109/07853890.2010.505931 588 K. Mustalahti et al. Key messages Abbreviations AU arbitrary unit • Celiac disease is a common disorder affec- CD celiac disease ting 1% of the European population. ELISA enzyme-linked immunosorbent assay • Celiac disease is underdiagnosed even in EMA endomysial antibodies European countries with high knowledge of KORA Co-operative Health Research in the Region the variable clinical picture of the disease. of Augsburg • The prevalence of celiac disease varies mark- MONICA multinational monitoring of trends and edly in different European countries. determinants in cardiovascular diseases tTG tissue transglutaminase (ELISA) test has proved to be a sensitive tool for CD The aims of the present study were: 1) to estab- detection, even in atypical or silent cases (3 – 6). It lish accurately the prevalence of CD in a large sam- is an accurate, observer-independent alternative to ple of the general European population, including serum IgA endomysial antibodies (EMA) detected both children and adults, using a centralized sero- by an indirect immunofl uorescence reaction, which logical screening approach; and 2) to investigate is a time-consuming and operator-dependent testing whether the prevalence of CD signifi cantly varies method. IgA class anti-tTG determination is between different areas of the European continent. currently considered as the best fi rst-step, CD We present here the fi nal results of this study, which screening test in the general population (7 – 10). was performed on the largest population sample However, the positive predictive value of tTG is not cross-sectionally screened for CD in the world very high, particularly when the pre-test probability ( n  29,212) by the serial determination of IgA-tTG of the disease is low, as in the screening of the general and IgA-EMA in anti-tTG-positive cases. population (9,11). Serum IgA-EMA is a more spe- cifi c marker of untreated CD (8,9). This autoanti- body also predicts the future development of mucosal Materials and methods lesions in individuals with normal small-bowel Study populations mucosal morphology (12 – 16). Therefore the serial determination of IgA-tTG and IgA-EMA (in anti- Sera from 29,212 individuals, both adults and chil- tTG-positive cases) is a powerful diagnostic algo- dren, from four European countries were sampled rithm for detecting CD, in terms of both sensitivity for serological studies (Table I). All sera were stored and specifi city (11,12,17,18). at  20 ° C/  70 ° C before serological testing. As indi- Despite these advances in CD detection, the over- cated below country by country, a proportion of all prevalence of the disease in Europe is still unclear. these sera were collected within the frame of other Early prevalence fi gures were based on clinical diag- studies (e.g. the MONICA study), but none of them noses, which relied upon the occurrence of gastroin- had already been investigated for CD serology. testinal symptoms and malabsorption. At that time many countries reported prevalence fi gures as low as Finland. A country-wide cross-sectional sample of 0.1% or less (19). Recent studies using serological 6,403 Finnish adults (30 – 93 years of age) represen- tests as the screening tool indicate that CD is highly tative of the Finnish urban and rural adult popula- underdiagnosed all over the world, with prevalence tion (3,279,772 inhabitants of this age group) was fi gures reaching 0.5% – 1.0% or even more (6,7,15, collected by two-stage cluster sampling as part of the 20 – 28). However, studies report considerable varia- Health 2000 survey in 2000 – 2001 co-ordinated by tion of the occurrence of the disease, both within and the National Public Health Institute of Finland (29). between different European countries. Since the Eligible population was 8,028 and participation rate sample sizes were often small as compared to the 80%. expected prevalence, the statistical power of available studies is limited. For this reason it is not clear Germany. Two different cross-sectional samples were whether different estimates refl ect by-chance vari- drawn from the population of Augsburg and two sur- ability or ‘ true ’ regional variation of disease preva- rounding counties (349,050 inhabitants of age group lence. It is worth noting that a precise estimate of the 25 – 74 years in 1990 and 357,627 inhabitants in European prevalence of CD is important not only for 2001) by sex-age stratifi ed two-stage cluster sam- epidemiological reasons but also for other aspects, pling (30,31). e.g. insurance, agricultural, international trade, and 1) A sample of 4,940 German adults (25 – 74 years regulatory issues within the European Union. of age) collected for the MONICA (multinational Celiac disease frequency in Europe 589 monitoring of trends and determinants in cardiovas- cular diseases) Augsburg population-based survey in 1989 – 1990 (30). Eligible population was 6,420 and participation rate 76.9%. Participants who refused to give blood or participants without enough serum for analysis were excluded ( n  307; 4.7%) leaving 4,633 participants for the analysis presented here. Follow-up data from anti-tTG-positive cases included in this subgroup of 4,633 participants have been described (31). 2) A sample of 4,261 German adults (25 – 74 years of age) collected for the KORA (Co-operative Health Research in the Region of Augsburg) population-based survey in 1999 – 2001 (32). Eligible population was 6,417 and participation rate 66.4%. Participants who refused to give blood or partici- pants without enough serum for analysis were excluded ( n  88; 1.4%), leaving 4,173 participants for the analysis presented here. Italy. A cross-sectional sample of 4,778 adults (20 – 100 years of age) and 2,649 children (0 – 16 years of age) was collected in three different surveys includ- ing all inhabitants of the village of Camerano (Ancona) in 2000 – 2002, inhabitants from the vil- lage Uri (Sassari) in 1999, and a school-child popu- lation aged 10 – 19 years attending the secondary school in Alghero (Sassari) in 1997 – 1999. Eligible population was altogether 11,978 and participation rate 62%. UK. The study population of the UK also consisted of two different samples: 1) Sera of 4,656 adults (25 – 64 years of age) from Belfast and surrounding district (223,575 inhabit- ants of this age group) were provided for this study from the MONICA 2 survey in 1986 – 1987 (33). Eligible population was 4,863 and participation rate 96%. 2) A sample of 1,975 children aged 12 and 15 years participating the Northern Ireland Younghearts 2000 Survey of risk factors for cardiovascular disease was collected in 2000. Eligible population was 2,017 and participation rate 98%. The details about the material collections have been published elsewhere (22,24). Study protocol The overall study protocol is described in Figure 1. Previously diagnosed CD cases, as well as individu- als on a gluten-free diet for other reasons than CD, were identifi ed by structured questionnaires, as a part of the original health surveys, and excluded from serological CD screening. Table I. Summary of the study results in the overall sample. Prevalence of CD with 95% confi dence interval (CI) is reported, based on different criteria: A  Previously diagnosed biopsy-proven CD patients  screening-detected tTG-positive cases; and B  Previously diagnosed biopsy-proven CD patients  cases with both tTG and EMA positivity. Previously tTG Individuals that Country, population Sample size diagnosed borderline but agreed to a Prevalence A % Prevalence B % (collection time) n/females (%) CD n tTG  n EMA  n EMA  n biopsy n (%) Biopsy  n (95% CI) (95% CI) Finland Adults (2000 – 2001) 6,403/3,527 (55) 38 120 3 87 63 (51) 47 2.5 (2.1 – 2.9) 2.0 (1.7 – 2.3) Germany Adults (1989 – 1990) 4,633/2,300 (50) 0 63 0 7 3 (5) 1 1.4 (1.1 – 1.7) 0.2 (0.1 – 0.3) Adults (1999 – 2001) 4,173/2,110 (51) 1 18 0 10 7 (39) 5 0.5 (0.3 – 0.7) 0.3 (0.1 – 0.5) Italy Adults (2000 – 2002) 4,781/2,716 (57) 1 65 0 32 42 (65) 23 1.4 (1.1 – 1.7) 0.7 (0.5 – 0.9) Children (1997 – 2002) 2,645/1,376 (52) 0 33 2 29 27 (77) 19 1.3 (0.9 – 1.7) 1.1 (0.7 – 1.5) UK Adults (1986 – 1987) 4,656/2,306 (50) 13 74 1 55 3 (4) 3 1.9 (1.5 – 2.3) 1.5 (1.1 – 1.9) Children (2000) 1,975/973 (49) 1 18 4 12 2 (9) 2 1.0 (0.6 – 1.4) 0.9 (0.5 – 1.3) Total 29,266/15,308 (52) 54 391 10 232 147 (38) 100 1.5 (1.4 – 1.7) 1.0 (0.9 – 1.1) Adults 24,646/12,959 (53) 53 340 4 191 118 (35) 79 1.6 (1.4 – 1.8) 1.0 (0.9 – 1.1) Children 4,620/2,349 (51) 1 51 6 41 29 (57) 21 1.1 (0.8 – 1.4) 0.9 (0.6 – 1.2) CD  celiac disease; tTG  tissue transglutaminase antibodies; EMA  endomysial antibodies. 590 K. Mustalahti et al. 29,274 participants Previously diagnosed CD (n = 54) and Individuals on a GFD because of other W7*DQWLERG\WHVWLQJ reasons than CD (n = 8) excluded n = 62 Positive tTG Bordeline tTG Cases negative for cases tTG not studied cases n = 384 further n = 391 n = 28,437 EMA+ Q  n = 232 Q  Q 6%%RIIHUHG 6%%RIIHUHG SHUIRUPHG SHUIRUPHG Figure 1. Study design. tTG  tissue transglutaminase; CD  celiac disease; GFD  gluten-free diet; EMA  endomysial antibodies; SBB  small-bowel biopsy. Serum tissue transglutaminase antibody testing time of the intestinal biopsy. Formalin-fi xed biopsy specimens (at least four specimens from both duode- All 29,212 sera were tested blindly for IgA class nal bulb and fi rst duodenal tract) were stained with tTG antibodies in the laboratory of Eurospital, Tri- hematoxylin and eosin. All biopsies were examined in este, Italy, using a human recombinant tTG-based a single center (Ancona) by a pathologist (I.B. and antibody kit (Eu-tTG ® system, Eurospital, Trieste, A.M.) who was not aware of the antibody test results. Italy). Validation by the manufacturer showed the According to the Marsh classifi cation (34) the histo- sensitivity of the kit in detecting EMA-positive sera logical damage was graded as I (infi ltrative lesion), II to be 98.2% and the specifi city 97.2%. The sensitiv- (infi ltrative-hyperplasic lesion), or III (partial or sub- ity of the kit in detecting biopsy-proven celiac dis- total villous atrophy with crypt hyperplasia). ease was 96.3% and the specifi city 84.7%. Cut-off All patients newly diagnosed with CD were pre- values were assigned as  7.0 AU/mL for negative scribed a gluten-free diet. results and  7.0 AU/mL for positives. In the pres- ent study titers between 5 and 6.9 AU/mL were Case defi nition considered border-line and were further tested for EMA. In this study we report two different CD-related prevalence fi gures: Serum endomysial antibody testing 1) Prevalence A: Previously diagnosed biopsy- proven (Marsh II or III) CD patients  screening- All tTG antibody-positive (  7.0 AU/mL) as well as detected anti-tTG-positive individuals. border-line titer sera (5 – 6.9 AU/mL) were further 2) Prevalence B: Previously diagnosed biopsy- tested for the presence of IgA-EMA with an indirect ® proven (Marsh II or III) CD patients  screening- immunofl uorescence (Antiendomysium , Eurospital detected individuals with both anti-tTG and EMA SpA, Trieste, Italy) performed by Eurospital, T rieste, positivity. Italy. A patient serum dilution titer of 1:  5 was considered positive. Statistical analyses Small-bowel biopsies Ninety-fi ve percent confi dence intervals (CI) for the prevalence fi gures obtained in different materials Confi rmation of the CD diagnosis by small-bowel p(1 p) biopsy was recommended to all anti-tTG antibody- were calculated as 1.96  where p is the positive individuals and to individuals showing N border-line anti-tTG antibodies associated with EMA proportion of positivity in the population and N is positivity. Gluten exposure was ascertained at the the sample size. 6%% 6%% 1RWVWXGLHGIXUWKHU (0$ (0$ (0$ VHUD Celiac disease frequency in Europe 591 Ethical aspects than in children (1.6 versus 1.1), while prevalence B was similar in both groups (1.0 in adults and 0.9 in The participants gave their written consent for the children, respectively). The prevalence of CD varied study. Local national ethical approval was obtained widely across countries, with the highest CD preva- by all centers involved in the study. The Helsinki lence being found in Finnish adults (prevalence Declaration was respected throughout the study. All A  2.5 and prevalence B  2.0), and the lowest in records and other information of the persons were one of the two German samples (prevalence A  0.5 stored according to the EU and national regulations. and prevalence B  0.3) (Table I). Since the population samples from different countries were not comparable for age range and Results time of sampling, we then analyzed CD prevalence Antibody positivity in the homogeneous subsample including only adults aged 30 – 64 years investigated during a short The data of antibody positivity, biopsy rates and time-span (1999 – 2002), to allow direct compari- results, and prevalence fi gures are shown in Table I. son of CD prevalence between different European In all materials there was somewhat more tTG pos- countries. The prevalence estimates in this subgroup itivity than EMA positivity. In all countries serum ( n  10,703) largely overlapped with those reported antibody screening detected a number of previously on the overall sample: overall prevalence A was undiagnosed cases. 1.4 (95% CI 1.2 – 1.6), and overall prevalence B was 1.0 (0.8 – 1.2). Again, a large inter-country variabil- Small-bowel biopsies ity was found, with a 5 – 8-fold difference between the country showing the highest CD prevalence Of all 401 autoantibody-positive individuals recom- (Finland, prevalence A  2.6% and prevalence mended for small-bowel biopsy, 147 (37%) agreed. B  2.4%) and the country showing the lowest CD Altogether 28 individuals had died after serum sam- prevalence (Germany, prevalence A  0.5% and pling, 128 refused, 49 could not be traced, and in prevalence B  0.3%) (Table II). 49 cases the local health care system or the family doctor did not fi nd the small-bowel biopsy necessary. In 100/147 (68%) biopsied persons the histologi- The size of the celiac iceberg in different cal analysis showed a typical CD enteropathy (grade European countries II or III Marsh lesion). Ninety-one of these were In the subgroup reported in Table II, the overall ratio both tTG and EMA antibody-positive, while nine between previously diagnosed CD cases ( n  29) and were anti-tTG antibody-positive but EMA-negative. the prevalence of CD (previously diagnosed  EMA Twenty-fi ve individuals showed minor changes in positives, n  139) was 0.21 (1 in 5). However this their small-bowel mucosal specimen (Marsh I lesion). proportion varied markedly between countries Fourteen of them were positive for both anti-tTG (Finland  0.24; Germany  0.12; Italy  0.06). and EMA antibodies, and 11 were positive for tTG but negative for EMA antibodies. Only 16 persons (11%) did not have any infl ammatory changes in Discussion their small-bowel mucosal specimen. Eight of these On a large population sample this study defi nitely had both antibody tests positivity, and eight were confi rms that CD is one of the commonest lifelong positive for tTG but negative for EMA antibodies. disorders in Europe, affecting around 1% of the gen- Six specimens (4%) were not valid for histological eral population in both children and adults. This inspection. estimate is now more accurate than previously avail- able data, for the following reasons: 1) it is the larg- est population sample ( n  29,266) so far investigated CD prevalence in Europe in the world. Only two CD screening studies had The prevalence of CD in the overall sample previously been conducted on more than 10,000 ( n  29,266) was 1.5% (prevalence A) and 1% (prev- subjects of the general population, one in Italy alence B), with a very narrow confi dence interval ( n  17,201) (35) and the other in the US ( n  12,678) (1.4 – 1.7 for prevalence A and 0.9 – 1.1 for prevalence (36); and 2) this is the fi rst study to be performed B, respectively). In all samples the prevalence fi gures in different European countries using the same diag- obtained by anti-tTG antibody positivity alone nostic algorithm and centrally performed determina- (prevalence A) were higher than those based on tions. We used the observer-independent serum combined anti-tTG and EMA antibody positivity IgA-tTG test based on human recombinant tTG for (prevalence B). Prevalence A was higher in adults the fi rst-level screening of CD because the test is 592 K. Mustalahti et al. accurate and easy to perform and it has shown high sensitivity in detecting untreated CD (3 – 10). European ring testing of CD-specifi c autoantibodies has shown differences in the results of antibody tests between different laboratories (37). Even minimal differences in the test performance may cause large differences in the number of subjects that have a positive test when screening the general population. Therefore we centralized the antibodies determina- tions, and all 29,212 sera were tested in the same laboratory. To increase the specifi city of the diagnos- tic procedure we performed also the EMA test in anti-tTG-positive or border-line samples, because there is evidence in the literature suggesting a higher positive predictive value of the EMA compared with the tTG test, particularly when the tTG titer is only modestly increased (9,11). Not only is CD very common in Europe, but it is also highly underdiagnosed in all countries — even in countries where there is traditionally a high knowl- edge of the disease (e.g. Finland). In our adult sub- sample we found that the ratio between the ‘ visible ’ (previously diagnosed) and the overall size (overall prevalence) of the celiac iceberg varied between 6% (Italy) and 24% (Finland). These results have implications affecting the European society from sev- eral points of view. Since untreated CD is associated with a number of complications (e.g. infertility and cancer) (1), the fi rst issue is how the diagnostic rate of this common disorder can be improved. The pros and cons of either CD mass screening or case fi nding have been recently reviewed (38). Case fi nding in at-risk individuals (e.g. subjects with anemia, chronic digestive complaints, or family history of CD) seen at the primary care level is a cheap and ethically sound approach to CD detection. In the US a case fi nding approach in the primary care setting increased the rate of diagnosis by 32- to 43-fold (39). However, the sensitivity of a case fi nding policy is low, as more than 50% are left undiagnosed (40). Although CD meets most of the WHO criteria for mass screening programs (41), controversies on diagnosis, poor understanding of the natural course of undiagnosed CD, and diffi culties with the adherence to a gluten- free diet all suggest caution before implementation of mass screening programs. A recent Markov model- based analysis showed that mass screening for CD of the young adult general population is associated with improved quality-adjusted life years (QALY) and becomes a cost-effective strategy if the time delay to diagnosis is longer than 6 years (42). Whatever diag- nostic strategy will eventually be shown to be supe- rior, our data clearly indicate that this common food intolerance deserves a high level of awareness in Europe because of its health, nutritional, social, psy- chological, and economic implications. Table II. Results of CD screening in adults aged 30 to 64 years investigated over a restricted time-span. Prevalence of CD with 95% confi dence interval (CI) is reported, based on different criteria: A  Previously diagnosed biopsy-proven CD patients  screening-detected tTG-positive cases; and B  Previously diagnosed biopsy-proven CD patients  cases with both anti-tTG and EMA positivity. Previously Individuals that Sample size diagnosed tTG border-line agreed to a Prevalence A Prevalence B n/females (%) CD n tTG  n EMA  n – but EMA  n biopsy n (%) Biopsy  n % (95 % CI) % (95 % CI) Finland (2000–2001) 4,846/2,548 (53) 27 100 83 3 55 (53) 40 2.6 (2.2–3.1) 2.4 (2.0–2.8) Germany (1999–2001) 3,098/1,574 (51) 1 14 7 0 6 (43) 0 0.5 (0.2–0.7) 0.3 (0.1–0.4) Italy (2000–2002) 2,759/1,606 (58) 1 31 17 0 25 (81) 12 1.2 (0.8–1.6) 0.7 (0.4–1.0) Total 10,703/5,728 (54) 29 145 107 3 86 (59) 52 1.4 (1.2–1.6) 1.0 (0.8–1.2) CD  celiac disease; tTG  transglutaminase antibodies; EMA  endomysial antibodies. Celiac disease frequency in Europe 593 Using homogeneous diagnostic criteria in adults patients with positive serology and normal histology. aged 30 – 64 years, this population-based screening Some of these could be true false positives and will study showed that the prevalence of CD in the adult lead to a possible over-estimation of CD prevalence, population varied markedly and signifi cantly in while the remainder may have true disease missed different European countries, with the highest on biopsy (potential CD). This level of uncertainty prevalence being found in Finland (2.4%) and the mostly applies to our prevalence A, which we con- lowest in Germany (0.3%) (Table II). The reasons sider less accurate than prevalence B, because many for these large between-country differences are not subjects showed isolated and modestly increased clear but could be related to both genetic and envi- anti-tTG positivity. Conversely, the possibility of a ronmental factors, such as the dietary pattern dur- false positivity of both tTG and EMA (not evolving ing infancy. Recent studies have shown that in overt CD with time) is still to be clearly docu- nutritional factors such as the duration of breast- mented in the literature. In our study antibody- feeding, age at gluten introduction, and amount of positive individuals were offered the opportunity for gluten introduced during the fi rst year of life can a small-bowel biopsy. The biopsy rate varied mark- infl uence not only the clinical presentation of the edly between different centers (from 77% in Italy to disease but also the overall prevalence of CD (25). 9% in the UK) mostly due to differences in the study Interestingly, no South-North geographical gradient populations. Especially in the old materials many was noted, as an intermediate CD prevalence was participants were untraceable, e.g. because of change found in the Southern country participating to this of address or death. Among traceable participants project (Italy, 0.7%). Then our results question the the main reasons for low biopsy rate was that either validity of an old theory relating CD prevalence in the family doctor did not fi nd the biopsy necessary Europe to past agriculture spreading. According to or participants refused the diagnostic procedure. this model, the slow spreading of gluten-rich cereals Altogether 68% of biopsied autoantibody-positive culture and consumption from the so-called ‘ fertile participants showed small-bowel mucosal changes crescent ’ area in the Near East exerted a negative typical for CD (Marsh II or III lesion). Based on our selective pressure on CD-predisposing genes during histological fi ndings, the previously reported risk of the last ten thousand years (43). Higher CD preva- patients ’ misclassifi cation applies to a maximum of lence should therefore be found in North European 20% of patients (the 9/141 with isolated anti-tTG countries, where gluten-rich cereals have been intro- positivity and Marsh II or III lesion, the 11/141 with duced more recently into the daily diet. This hypoth- isolated anti-tTG positivity and Marsh I lesion, plus esis was not confi rmed by our data, as we found that the 8/141 with anti-tTG positivity and normal the country reached earlier by agriculture practices histology). (Italy) showed higher CD prevalence than Germany, We are aware of the possible limitations of this an area colonized by farmers later on. study: 1) With the exception of Finland, the sam- It is important to note that the case defi nition pling criteria were not homogeneous for geographic infl uences prevalence estimates in epidemiological and age distribution of sampled individuals. There studies. Whatever case defi nition is preferred, there was under-representation of children in some coun- is a risk of patient misclassifi cation. This issue is par- tries. For this reason we restricted between-country ticularly important for CD, a widely variable disor- comparisons of CD prevalence to a well defi ned age der including cases with positive serology and normal range (30 – 64 years). 2) The occasional patient with histology (potential CD) (13) and cases with nega- IgA defi ciency and CD would have been missed by tive serology and positive histology (seronegative our IgA-based anti-tTG and EMA screening algo- CD) (44). Although the small-intestinal biopsy has rithm. 3) The MONICA materials from Germany an indisputable diagnostic role in the clinical setting, and the UK were collected earlier than other sera. this invasive investigation is not an essential require- This could infl uence our overall epidemiological ment for an epidemiological survey. As a matter of fi ndings reported in Table I, as it has been reported fact, in many recently published epidemiological that CD prevalence could change (increase) over studies the antibody positivity has been considered time (36,45). 4) The number of previously diag- as the only criterion for CD diagnosis (22 – 24). A nosed CD cases was identifi ed by questionnaires as a CD prevalence study based on serological screening part of the original health surveys. Since there could presents factors that could lead to slight over- or be an ascertainment bias in MONICA individuals under-estimation of CD prevalence. Since the sensi- investigated years before, we restricted the analy- tivity of serology is lower in patients showing a mod- sis of the diagnosed/undiagnosed ratio (celiac ice- est degree of intestinal damage (e.g. Marsh I lesion) berg) to the de novo investigated subjects (Table II). (44), serological screening may under-estimate the And 5) the ratio between anti-tTG and EMA ‘ true ’ prevalence. On the other hand, there are positivity was around 1.5 in most national samples, 594 K. Mustalahti et al. suggesting the possible ‘ false ’ positivity of low-titer Pathology, Universit à Politecnica delle Marche, anti-tTG. However in the German material collected Ancona, Italy, Zentrum M ü nchen, German in 1989 – 1990 the number of anti-tTG-positive Research Center for Environmental Health, Institute sera was ten times higher than EMA (Table I), for rea- of Epidemiology, Germany sons that remain unclear. We hypothesize that these old German samples underwent dehydration during Declaration of interest: The authors report no storage affecting the tTG quantitative determination confl icts of interest. The authors alone are respon- but not the semi-quantitative EMA test performed by sible for the content and writing of the paper. indirect immunofl uorescence. In the end, this outlier Maurizio Gasparin and Enzo Bravi are employees result had poor infl uence on CD prevalence B shown of Eurospital SpA, Trieste, Italy. They did not receive in Table I (including only EMA-positive cases) and any fi nancial support or other credits for this work. none on the data presented in Table II. In conclusion, this study defi nitely confi rms that CD is one of the commonest lifelong disorders References affecting around 1% of the European population. 1. Green PH, Jabri B. Coeliac disease. Lancet. 2003;362: The disease is still heavily underdiagnosed in all 383 – 91. European countries. Quite surprisingly, we found a 2. Collin P, Kaukinen K, V ä lim ä ki M, Salmi J. Endocrinologi- huge difference in CD prevalence between Euro- cal disorders and celiac disease. Endocr Rev. 2002;23: pean countries (8-fold in our samples). Environ- 464 – 83. 3. Dieterich W, Laag E, Sch ö pper H, Volta U, Ferguson A, mental factors responsible for the wide variability Gillett H, et al. Autoantibodies to tissue transglutaminase of CD prevalence between European countries as predictors of celiac disease. Gastroenterology. 1998;115: need further investigation, as this knowledge could 1317 – 21. pave the way to primary prevention of this lifelong 4. B ü rgin-Wolff A, Dahlbom I, Hadziselimovic F, petersson CJ. disorder. Antibodies against human tissue transglutaminase and endo- mysium in diagnosing and monitoring coeliac disease. Scand J Gastroenterol. 2002;37:685 – 91. Acknowledgements 5. Van-Meensel B, Hiele M, Hoffman I, Vermeire S, Rutgeerts P, Geboes K, et al. Diagnsotic accuracy of ten second- This work was supported by the Commission of generation (human) tissue transglutaminase antibody assays the European Communities, the specifi c RTD pro- in celiac disease. Clin Chem. 2004;50:2125 – 35. 6. Fabiani E, Peruzzi E, Mandolesi A, Garbuglia G, Fanciulli gram ‘ Quality of Life and Management of Living G, D ’ Appello AR, et al. anti-human versus anti-guinea pig Resources ’ , QLRT-1999-00037, ‘ Evaluation of the tissue transglutaminase antibodies as the fi rst-level serologi- prevalence of celiac disease and its genetic com- cal screening test for coeliac disease in the general popula- ponents in the European population ’ . The study tion. Dig Liver Dis. 2004;36:671 – 6. does not necessarily refl ect its views and in no 7. Akbari MR, Mohammadkhani A, Fakheri H, Javad Zahedi M, Shahbazkhani B, Nouraie M, et al. Screening of the way anticipates the Commission ’ s future policy in adult population in Iran for coeliac disease: comparison of this area. Further, this study was fi nancially sup- the tissue-transglutaminase antibody and anti-endomysial ported by Research Council for Health, Academy of antibody test. Eur J Gastroenterol Hepatol. 2006;18: Finland. 1181 – 6. 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Laurila K, et al. Immunoglobulin A autoantibodies against 31. Metzger MH, Heier M, M ä ki M, Bravi E, Schneider A, transglutaminase 2 in the small intestinal mucosa predict L ö wel H, et al. Mortality excess in individuals with elevated forthcoming coeliac disease. Aliment Pharmacol Ther. IgA anti-transglutaminase antibodies: the KORA/MONICA 2006;24:541 – 52. Augsburg cohort study 1989 – 1998. Eur J Epidemiol. 2006; 17. West J, Lloyd CA, Hill PG, Holmes GK. IgA-antitissue 21:359 – 65. transglutaminase: validation of a commercial assay for diag- 32. Holle R, Happich M, Lowel H, Wichmann HE. KORA — a nosing coeliac disease. Clin Lab. 2002;48:241 – 6. research platform for population based health research. 18. Walker MM, Murray JA, Ronkainen J, Aro P, Storskrubb T, Gesundheitswesen. 2005;67 Suppl 1:S19 – 25. D ’ Amato M, et al. Detection of celiac disease and lymphocytic 33. 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Basel: Karger; 1992. p. 25 – 44. centre antigliadin antibodies screening for coeliac disease in 20. Catassi C, R ä tsch IM, Fabiani E, Rossini M, Bordicchia F, school-age subjects. Acta Paediatr Suppl. 1996;412:29 – 35. Candela F, et al. Celiac disease in the year 2000: exploring 36. Rubio-Tapia A, Kyle RA, Kaplan ER, Johnson DR, Page W, the iceberg. Lancet. 1994;343:200 – 3. Erdtmann F, et al. Increased prevalence and mortality in undi- 21. Csizmadia C, Mearin M, von Blomberg B, Brand R, agnosed celiac disease. Gastroenterology. 2009;137:88 – 93. Verloove-Vanhorick S. An iceberg of childhood coeliac 37. Stern M. Comparative evaluation of serologic tests for celiac disease in the Netherlands. Lancet. 1999;353:813 – 4. disease: A European initiative toward standardization. J Pedi- 22. West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, atr Gastroenterol Nutr. 2000;31:513 – 9. et al. Seroprevalence, correlates, and characteristics of unde- 38. F asano A, Evans K. 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Carlsson A, Agardh D, Borulf S, Grodzinsky E, Axelsson I, 41. Fasano A. Should we screen for celiac disease? Yes. BMJ. Ivarsson A. Prevalence of celiac disease: before and after a 2009;339:b3592. national change in feeding recommendations. Scand J Gas- 42. Hershcovici T, Leshno M, Goldin E, Shamir R, Israeli E. Cost troenterol. 2006;41:553 – 8. effectiveness of mass screening for coeliac disease is deter- 26. Dube C, Rostom A, Sy R, Saloojee N, Garritty C, Sampson mined by time-delay to diagnosis and quality of life on a glu- M, et al. The prevalence of celiac disease in average-risk and ten free diet. Aliment Pharmacol Ther. 2010; 31:901 – 10 . at-risk Western European populations: a systematic review. 43. Cronin CC, Shanahan F. Why is celiac disease so common Gastroenterology. 2005;128:S57 – 67. in Ireland? Perspect Biol Med. 2001;44:342 – 52. 27. Henker J, Losel A, Conrad K, Hirsch T, Leupold W. Preva- 44. Salmi TT, Collin P, Korponay-Szabo IR, Laurila K, Partanen lence of asymptomatic coeliac disease in children and adults J, Huhtala H, et al. Endomysial antibody-negative celiac in Dresden region of Germany. Dtsch Med Wochenschr. disease: clinical characteristics and intestinal autoantibody 2002;127:511 – 5. deposits. Gut. 2006;55:1746 – 53. 28. Johnston SD, Watson RG, McMillan SA, Sloan J, Love AH. 45. Lohi S, Mustalahti K, Kaukinen K, Laurila K, Collin P, Prevalence of coeliac disease in Northern Ireland. Lancet. Rissanen H, et al. Increasing prevalence of celiac disease over 1997;350:1370. time. Aliment Pharmacol Ther. 2007;26:1217 – 25. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Medicine Taylor & Francis

The prevalence of celiac disease in Europe: Results of a centralized, international mass screening project

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Taylor & Francis
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© 2010 Informa UK, Ltd.
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1365-2060
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0785-3890
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10.3109/07853890.2010.505931
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Abstract

Introduction. Although the prevalence of celiac disease (CD) has been extensively investigated in recent years, an accurate estimate of CD frequency in the European population is still lacking. The aims of this study were: 1) to establish accurately the prevalence of CD in a large sample of the European population (Finland, Germany, Italy, and UK), including both children and adults; and 2) to investigate whether the prevalence of CD signifi cantly varies between different areas of the European continent. Materials and methods. Samples were drawn from the four populations. All 29,212 participants were tested for CD by tissue transglutaminase (tTG) antibody test. Positive and border-line fi ndings were further tested for serum endomysial antibodies (EMA). All serological determinations were centrally performed. Small-bowel biopsies were recommended to autoantibody- positive individuals. Previously diagnosed cases were identifi ed. Results. The overall CD prevalence (previously diagnosed plus anti-tTG and EMA positives) was 1.0% (95% CI 0.9 – 1.1). In subjects aged 30 – 64 years CD prevalence was 2.4% in Finland (2.0 – 2.8), 0.3% in Germany (0.1 – 0.4), and 0.7% in Italy (0.4 – 1.0). Sixty-eight percent of antibody-positive individuals showed small-bowel mucosal changes typical for CD (Marsh II/III lesion). Conclusions. CD is common in Europe. CD prevalence shows large unexplained differences in adult age across different European countries. Key words: Anti-transglutaminase antibodies , celiac disease , epidemiology , population-based screening , prevalence be even totally absent despite the presence of the Introduction mucosal lesion. Patients may be clinically silent Celiac disease (CD) is an autoimmune disorder for years or decades or present only extraintestinal triggered by gluten, the major protein complex found complications, such as osteoporosis, dental enamel in wheat, barley, and rye, in genetically predisposed defects, or peripheral or central nervous system individuals (1). The major problem in diagnosing the involvement (2). disease is its multifaceted clinical picture. Gastroin- Serum IgA class tissue transglutaminase (tTG) testinal symptoms may vary from mild to severe or antibody enzyme-linked immunosorbent assay Correspondence: Professor Carlo Catassi, Department of Pediatrics, Università Politecnica delle Marche, Via Corridoni 11, 60123 Ancona, Italy. Fax: +39 071 36281. E-mail: [email protected] (Received 10 March 2009; accepted 30 June 2010) ISSN 0785-3890 print/ISSN 1365-2060 online © 2010 Informa UK Ltd. DOI: 10.3109/07853890.2010.505931 588 K. Mustalahti et al. Key messages Abbreviations AU arbitrary unit • Celiac disease is a common disorder affec- CD celiac disease ting 1% of the European population. ELISA enzyme-linked immunosorbent assay • Celiac disease is underdiagnosed even in EMA endomysial antibodies European countries with high knowledge of KORA Co-operative Health Research in the Region the variable clinical picture of the disease. of Augsburg • The prevalence of celiac disease varies mark- MONICA multinational monitoring of trends and edly in different European countries. determinants in cardiovascular diseases tTG tissue transglutaminase (ELISA) test has proved to be a sensitive tool for CD The aims of the present study were: 1) to estab- detection, even in atypical or silent cases (3 – 6). It lish accurately the prevalence of CD in a large sam- is an accurate, observer-independent alternative to ple of the general European population, including serum IgA endomysial antibodies (EMA) detected both children and adults, using a centralized sero- by an indirect immunofl uorescence reaction, which logical screening approach; and 2) to investigate is a time-consuming and operator-dependent testing whether the prevalence of CD signifi cantly varies method. IgA class anti-tTG determination is between different areas of the European continent. currently considered as the best fi rst-step, CD We present here the fi nal results of this study, which screening test in the general population (7 – 10). was performed on the largest population sample However, the positive predictive value of tTG is not cross-sectionally screened for CD in the world very high, particularly when the pre-test probability ( n  29,212) by the serial determination of IgA-tTG of the disease is low, as in the screening of the general and IgA-EMA in anti-tTG-positive cases. population (9,11). Serum IgA-EMA is a more spe- cifi c marker of untreated CD (8,9). This autoanti- body also predicts the future development of mucosal Materials and methods lesions in individuals with normal small-bowel Study populations mucosal morphology (12 – 16). Therefore the serial determination of IgA-tTG and IgA-EMA (in anti- Sera from 29,212 individuals, both adults and chil- tTG-positive cases) is a powerful diagnostic algo- dren, from four European countries were sampled rithm for detecting CD, in terms of both sensitivity for serological studies (Table I). All sera were stored and specifi city (11,12,17,18). at  20 ° C/  70 ° C before serological testing. As indi- Despite these advances in CD detection, the over- cated below country by country, a proportion of all prevalence of the disease in Europe is still unclear. these sera were collected within the frame of other Early prevalence fi gures were based on clinical diag- studies (e.g. the MONICA study), but none of them noses, which relied upon the occurrence of gastroin- had already been investigated for CD serology. testinal symptoms and malabsorption. At that time many countries reported prevalence fi gures as low as Finland. A country-wide cross-sectional sample of 0.1% or less (19). Recent studies using serological 6,403 Finnish adults (30 – 93 years of age) represen- tests as the screening tool indicate that CD is highly tative of the Finnish urban and rural adult popula- underdiagnosed all over the world, with prevalence tion (3,279,772 inhabitants of this age group) was fi gures reaching 0.5% – 1.0% or even more (6,7,15, collected by two-stage cluster sampling as part of the 20 – 28). However, studies report considerable varia- Health 2000 survey in 2000 – 2001 co-ordinated by tion of the occurrence of the disease, both within and the National Public Health Institute of Finland (29). between different European countries. Since the Eligible population was 8,028 and participation rate sample sizes were often small as compared to the 80%. expected prevalence, the statistical power of available studies is limited. For this reason it is not clear Germany. Two different cross-sectional samples were whether different estimates refl ect by-chance vari- drawn from the population of Augsburg and two sur- ability or ‘ true ’ regional variation of disease preva- rounding counties (349,050 inhabitants of age group lence. It is worth noting that a precise estimate of the 25 – 74 years in 1990 and 357,627 inhabitants in European prevalence of CD is important not only for 2001) by sex-age stratifi ed two-stage cluster sam- epidemiological reasons but also for other aspects, pling (30,31). e.g. insurance, agricultural, international trade, and 1) A sample of 4,940 German adults (25 – 74 years regulatory issues within the European Union. of age) collected for the MONICA (multinational Celiac disease frequency in Europe 589 monitoring of trends and determinants in cardiovas- cular diseases) Augsburg population-based survey in 1989 – 1990 (30). Eligible population was 6,420 and participation rate 76.9%. Participants who refused to give blood or participants without enough serum for analysis were excluded ( n  307; 4.7%) leaving 4,633 participants for the analysis presented here. Follow-up data from anti-tTG-positive cases included in this subgroup of 4,633 participants have been described (31). 2) A sample of 4,261 German adults (25 – 74 years of age) collected for the KORA (Co-operative Health Research in the Region of Augsburg) population-based survey in 1999 – 2001 (32). Eligible population was 6,417 and participation rate 66.4%. Participants who refused to give blood or partici- pants without enough serum for analysis were excluded ( n  88; 1.4%), leaving 4,173 participants for the analysis presented here. Italy. A cross-sectional sample of 4,778 adults (20 – 100 years of age) and 2,649 children (0 – 16 years of age) was collected in three different surveys includ- ing all inhabitants of the village of Camerano (Ancona) in 2000 – 2002, inhabitants from the vil- lage Uri (Sassari) in 1999, and a school-child popu- lation aged 10 – 19 years attending the secondary school in Alghero (Sassari) in 1997 – 1999. Eligible population was altogether 11,978 and participation rate 62%. UK. The study population of the UK also consisted of two different samples: 1) Sera of 4,656 adults (25 – 64 years of age) from Belfast and surrounding district (223,575 inhabit- ants of this age group) were provided for this study from the MONICA 2 survey in 1986 – 1987 (33). Eligible population was 4,863 and participation rate 96%. 2) A sample of 1,975 children aged 12 and 15 years participating the Northern Ireland Younghearts 2000 Survey of risk factors for cardiovascular disease was collected in 2000. Eligible population was 2,017 and participation rate 98%. The details about the material collections have been published elsewhere (22,24). Study protocol The overall study protocol is described in Figure 1. Previously diagnosed CD cases, as well as individu- als on a gluten-free diet for other reasons than CD, were identifi ed by structured questionnaires, as a part of the original health surveys, and excluded from serological CD screening. Table I. Summary of the study results in the overall sample. Prevalence of CD with 95% confi dence interval (CI) is reported, based on different criteria: A  Previously diagnosed biopsy-proven CD patients  screening-detected tTG-positive cases; and B  Previously diagnosed biopsy-proven CD patients  cases with both tTG and EMA positivity. Previously tTG Individuals that Country, population Sample size diagnosed borderline but agreed to a Prevalence A % Prevalence B % (collection time) n/females (%) CD n tTG  n EMA  n EMA  n biopsy n (%) Biopsy  n (95% CI) (95% CI) Finland Adults (2000 – 2001) 6,403/3,527 (55) 38 120 3 87 63 (51) 47 2.5 (2.1 – 2.9) 2.0 (1.7 – 2.3) Germany Adults (1989 – 1990) 4,633/2,300 (50) 0 63 0 7 3 (5) 1 1.4 (1.1 – 1.7) 0.2 (0.1 – 0.3) Adults (1999 – 2001) 4,173/2,110 (51) 1 18 0 10 7 (39) 5 0.5 (0.3 – 0.7) 0.3 (0.1 – 0.5) Italy Adults (2000 – 2002) 4,781/2,716 (57) 1 65 0 32 42 (65) 23 1.4 (1.1 – 1.7) 0.7 (0.5 – 0.9) Children (1997 – 2002) 2,645/1,376 (52) 0 33 2 29 27 (77) 19 1.3 (0.9 – 1.7) 1.1 (0.7 – 1.5) UK Adults (1986 – 1987) 4,656/2,306 (50) 13 74 1 55 3 (4) 3 1.9 (1.5 – 2.3) 1.5 (1.1 – 1.9) Children (2000) 1,975/973 (49) 1 18 4 12 2 (9) 2 1.0 (0.6 – 1.4) 0.9 (0.5 – 1.3) Total 29,266/15,308 (52) 54 391 10 232 147 (38) 100 1.5 (1.4 – 1.7) 1.0 (0.9 – 1.1) Adults 24,646/12,959 (53) 53 340 4 191 118 (35) 79 1.6 (1.4 – 1.8) 1.0 (0.9 – 1.1) Children 4,620/2,349 (51) 1 51 6 41 29 (57) 21 1.1 (0.8 – 1.4) 0.9 (0.6 – 1.2) CD  celiac disease; tTG  tissue transglutaminase antibodies; EMA  endomysial antibodies. 590 K. Mustalahti et al. 29,274 participants Previously diagnosed CD (n = 54) and Individuals on a GFD because of other W7*DQWLERG\WHVWLQJ reasons than CD (n = 8) excluded n = 62 Positive tTG Bordeline tTG Cases negative for cases tTG not studied cases n = 384 further n = 391 n = 28,437 EMA+ Q  n = 232 Q  Q 6%%RIIHUHG 6%%RIIHUHG SHUIRUPHG SHUIRUPHG Figure 1. Study design. tTG  tissue transglutaminase; CD  celiac disease; GFD  gluten-free diet; EMA  endomysial antibodies; SBB  small-bowel biopsy. Serum tissue transglutaminase antibody testing time of the intestinal biopsy. Formalin-fi xed biopsy specimens (at least four specimens from both duode- All 29,212 sera were tested blindly for IgA class nal bulb and fi rst duodenal tract) were stained with tTG antibodies in the laboratory of Eurospital, Tri- hematoxylin and eosin. All biopsies were examined in este, Italy, using a human recombinant tTG-based a single center (Ancona) by a pathologist (I.B. and antibody kit (Eu-tTG ® system, Eurospital, Trieste, A.M.) who was not aware of the antibody test results. Italy). Validation by the manufacturer showed the According to the Marsh classifi cation (34) the histo- sensitivity of the kit in detecting EMA-positive sera logical damage was graded as I (infi ltrative lesion), II to be 98.2% and the specifi city 97.2%. The sensitiv- (infi ltrative-hyperplasic lesion), or III (partial or sub- ity of the kit in detecting biopsy-proven celiac dis- total villous atrophy with crypt hyperplasia). ease was 96.3% and the specifi city 84.7%. Cut-off All patients newly diagnosed with CD were pre- values were assigned as  7.0 AU/mL for negative scribed a gluten-free diet. results and  7.0 AU/mL for positives. In the pres- ent study titers between 5 and 6.9 AU/mL were Case defi nition considered border-line and were further tested for EMA. In this study we report two different CD-related prevalence fi gures: Serum endomysial antibody testing 1) Prevalence A: Previously diagnosed biopsy- proven (Marsh II or III) CD patients  screening- All tTG antibody-positive (  7.0 AU/mL) as well as detected anti-tTG-positive individuals. border-line titer sera (5 – 6.9 AU/mL) were further 2) Prevalence B: Previously diagnosed biopsy- tested for the presence of IgA-EMA with an indirect ® proven (Marsh II or III) CD patients  screening- immunofl uorescence (Antiendomysium , Eurospital detected individuals with both anti-tTG and EMA SpA, Trieste, Italy) performed by Eurospital, T rieste, positivity. Italy. A patient serum dilution titer of 1:  5 was considered positive. Statistical analyses Small-bowel biopsies Ninety-fi ve percent confi dence intervals (CI) for the prevalence fi gures obtained in different materials Confi rmation of the CD diagnosis by small-bowel p(1 p) biopsy was recommended to all anti-tTG antibody- were calculated as 1.96  where p is the positive individuals and to individuals showing N border-line anti-tTG antibodies associated with EMA proportion of positivity in the population and N is positivity. Gluten exposure was ascertained at the the sample size. 6%% 6%% 1RWVWXGLHGIXUWKHU (0$ (0$ (0$ VHUD Celiac disease frequency in Europe 591 Ethical aspects than in children (1.6 versus 1.1), while prevalence B was similar in both groups (1.0 in adults and 0.9 in The participants gave their written consent for the children, respectively). The prevalence of CD varied study. Local national ethical approval was obtained widely across countries, with the highest CD preva- by all centers involved in the study. The Helsinki lence being found in Finnish adults (prevalence Declaration was respected throughout the study. All A  2.5 and prevalence B  2.0), and the lowest in records and other information of the persons were one of the two German samples (prevalence A  0.5 stored according to the EU and national regulations. and prevalence B  0.3) (Table I). Since the population samples from different countries were not comparable for age range and Results time of sampling, we then analyzed CD prevalence Antibody positivity in the homogeneous subsample including only adults aged 30 – 64 years investigated during a short The data of antibody positivity, biopsy rates and time-span (1999 – 2002), to allow direct compari- results, and prevalence fi gures are shown in Table I. son of CD prevalence between different European In all materials there was somewhat more tTG pos- countries. The prevalence estimates in this subgroup itivity than EMA positivity. In all countries serum ( n  10,703) largely overlapped with those reported antibody screening detected a number of previously on the overall sample: overall prevalence A was undiagnosed cases. 1.4 (95% CI 1.2 – 1.6), and overall prevalence B was 1.0 (0.8 – 1.2). Again, a large inter-country variabil- Small-bowel biopsies ity was found, with a 5 – 8-fold difference between the country showing the highest CD prevalence Of all 401 autoantibody-positive individuals recom- (Finland, prevalence A  2.6% and prevalence mended for small-bowel biopsy, 147 (37%) agreed. B  2.4%) and the country showing the lowest CD Altogether 28 individuals had died after serum sam- prevalence (Germany, prevalence A  0.5% and pling, 128 refused, 49 could not be traced, and in prevalence B  0.3%) (Table II). 49 cases the local health care system or the family doctor did not fi nd the small-bowel biopsy necessary. In 100/147 (68%) biopsied persons the histologi- The size of the celiac iceberg in different cal analysis showed a typical CD enteropathy (grade European countries II or III Marsh lesion). Ninety-one of these were In the subgroup reported in Table II, the overall ratio both tTG and EMA antibody-positive, while nine between previously diagnosed CD cases ( n  29) and were anti-tTG antibody-positive but EMA-negative. the prevalence of CD (previously diagnosed  EMA Twenty-fi ve individuals showed minor changes in positives, n  139) was 0.21 (1 in 5). However this their small-bowel mucosal specimen (Marsh I lesion). proportion varied markedly between countries Fourteen of them were positive for both anti-tTG (Finland  0.24; Germany  0.12; Italy  0.06). and EMA antibodies, and 11 were positive for tTG but negative for EMA antibodies. Only 16 persons (11%) did not have any infl ammatory changes in Discussion their small-bowel mucosal specimen. Eight of these On a large population sample this study defi nitely had both antibody tests positivity, and eight were confi rms that CD is one of the commonest lifelong positive for tTG but negative for EMA antibodies. disorders in Europe, affecting around 1% of the gen- Six specimens (4%) were not valid for histological eral population in both children and adults. This inspection. estimate is now more accurate than previously avail- able data, for the following reasons: 1) it is the larg- est population sample ( n  29,266) so far investigated CD prevalence in Europe in the world. Only two CD screening studies had The prevalence of CD in the overall sample previously been conducted on more than 10,000 ( n  29,266) was 1.5% (prevalence A) and 1% (prev- subjects of the general population, one in Italy alence B), with a very narrow confi dence interval ( n  17,201) (35) and the other in the US ( n  12,678) (1.4 – 1.7 for prevalence A and 0.9 – 1.1 for prevalence (36); and 2) this is the fi rst study to be performed B, respectively). In all samples the prevalence fi gures in different European countries using the same diag- obtained by anti-tTG antibody positivity alone nostic algorithm and centrally performed determina- (prevalence A) were higher than those based on tions. We used the observer-independent serum combined anti-tTG and EMA antibody positivity IgA-tTG test based on human recombinant tTG for (prevalence B). Prevalence A was higher in adults the fi rst-level screening of CD because the test is 592 K. Mustalahti et al. accurate and easy to perform and it has shown high sensitivity in detecting untreated CD (3 – 10). European ring testing of CD-specifi c autoantibodies has shown differences in the results of antibody tests between different laboratories (37). Even minimal differences in the test performance may cause large differences in the number of subjects that have a positive test when screening the general population. Therefore we centralized the antibodies determina- tions, and all 29,212 sera were tested in the same laboratory. To increase the specifi city of the diagnos- tic procedure we performed also the EMA test in anti-tTG-positive or border-line samples, because there is evidence in the literature suggesting a higher positive predictive value of the EMA compared with the tTG test, particularly when the tTG titer is only modestly increased (9,11). Not only is CD very common in Europe, but it is also highly underdiagnosed in all countries — even in countries where there is traditionally a high knowl- edge of the disease (e.g. Finland). In our adult sub- sample we found that the ratio between the ‘ visible ’ (previously diagnosed) and the overall size (overall prevalence) of the celiac iceberg varied between 6% (Italy) and 24% (Finland). These results have implications affecting the European society from sev- eral points of view. Since untreated CD is associated with a number of complications (e.g. infertility and cancer) (1), the fi rst issue is how the diagnostic rate of this common disorder can be improved. The pros and cons of either CD mass screening or case fi nding have been recently reviewed (38). Case fi nding in at-risk individuals (e.g. subjects with anemia, chronic digestive complaints, or family history of CD) seen at the primary care level is a cheap and ethically sound approach to CD detection. In the US a case fi nding approach in the primary care setting increased the rate of diagnosis by 32- to 43-fold (39). However, the sensitivity of a case fi nding policy is low, as more than 50% are left undiagnosed (40). Although CD meets most of the WHO criteria for mass screening programs (41), controversies on diagnosis, poor understanding of the natural course of undiagnosed CD, and diffi culties with the adherence to a gluten- free diet all suggest caution before implementation of mass screening programs. A recent Markov model- based analysis showed that mass screening for CD of the young adult general population is associated with improved quality-adjusted life years (QALY) and becomes a cost-effective strategy if the time delay to diagnosis is longer than 6 years (42). Whatever diag- nostic strategy will eventually be shown to be supe- rior, our data clearly indicate that this common food intolerance deserves a high level of awareness in Europe because of its health, nutritional, social, psy- chological, and economic implications. Table II. Results of CD screening in adults aged 30 to 64 years investigated over a restricted time-span. Prevalence of CD with 95% confi dence interval (CI) is reported, based on different criteria: A  Previously diagnosed biopsy-proven CD patients  screening-detected tTG-positive cases; and B  Previously diagnosed biopsy-proven CD patients  cases with both anti-tTG and EMA positivity. Previously Individuals that Sample size diagnosed tTG border-line agreed to a Prevalence A Prevalence B n/females (%) CD n tTG  n EMA  n – but EMA  n biopsy n (%) Biopsy  n % (95 % CI) % (95 % CI) Finland (2000–2001) 4,846/2,548 (53) 27 100 83 3 55 (53) 40 2.6 (2.2–3.1) 2.4 (2.0–2.8) Germany (1999–2001) 3,098/1,574 (51) 1 14 7 0 6 (43) 0 0.5 (0.2–0.7) 0.3 (0.1–0.4) Italy (2000–2002) 2,759/1,606 (58) 1 31 17 0 25 (81) 12 1.2 (0.8–1.6) 0.7 (0.4–1.0) Total 10,703/5,728 (54) 29 145 107 3 86 (59) 52 1.4 (1.2–1.6) 1.0 (0.8–1.2) CD  celiac disease; tTG  transglutaminase antibodies; EMA  endomysial antibodies. Celiac disease frequency in Europe 593 Using homogeneous diagnostic criteria in adults patients with positive serology and normal histology. aged 30 – 64 years, this population-based screening Some of these could be true false positives and will study showed that the prevalence of CD in the adult lead to a possible over-estimation of CD prevalence, population varied markedly and signifi cantly in while the remainder may have true disease missed different European countries, with the highest on biopsy (potential CD). This level of uncertainty prevalence being found in Finland (2.4%) and the mostly applies to our prevalence A, which we con- lowest in Germany (0.3%) (Table II). The reasons sider less accurate than prevalence B, because many for these large between-country differences are not subjects showed isolated and modestly increased clear but could be related to both genetic and envi- anti-tTG positivity. Conversely, the possibility of a ronmental factors, such as the dietary pattern dur- false positivity of both tTG and EMA (not evolving ing infancy. Recent studies have shown that in overt CD with time) is still to be clearly docu- nutritional factors such as the duration of breast- mented in the literature. In our study antibody- feeding, age at gluten introduction, and amount of positive individuals were offered the opportunity for gluten introduced during the fi rst year of life can a small-bowel biopsy. The biopsy rate varied mark- infl uence not only the clinical presentation of the edly between different centers (from 77% in Italy to disease but also the overall prevalence of CD (25). 9% in the UK) mostly due to differences in the study Interestingly, no South-North geographical gradient populations. Especially in the old materials many was noted, as an intermediate CD prevalence was participants were untraceable, e.g. because of change found in the Southern country participating to this of address or death. Among traceable participants project (Italy, 0.7%). Then our results question the the main reasons for low biopsy rate was that either validity of an old theory relating CD prevalence in the family doctor did not fi nd the biopsy necessary Europe to past agriculture spreading. According to or participants refused the diagnostic procedure. this model, the slow spreading of gluten-rich cereals Altogether 68% of biopsied autoantibody-positive culture and consumption from the so-called ‘ fertile participants showed small-bowel mucosal changes crescent ’ area in the Near East exerted a negative typical for CD (Marsh II or III lesion). Based on our selective pressure on CD-predisposing genes during histological fi ndings, the previously reported risk of the last ten thousand years (43). Higher CD preva- patients ’ misclassifi cation applies to a maximum of lence should therefore be found in North European 20% of patients (the 9/141 with isolated anti-tTG countries, where gluten-rich cereals have been intro- positivity and Marsh II or III lesion, the 11/141 with duced more recently into the daily diet. This hypoth- isolated anti-tTG positivity and Marsh I lesion, plus esis was not confi rmed by our data, as we found that the 8/141 with anti-tTG positivity and normal the country reached earlier by agriculture practices histology). (Italy) showed higher CD prevalence than Germany, We are aware of the possible limitations of this an area colonized by farmers later on. study: 1) With the exception of Finland, the sam- It is important to note that the case defi nition pling criteria were not homogeneous for geographic infl uences prevalence estimates in epidemiological and age distribution of sampled individuals. There studies. Whatever case defi nition is preferred, there was under-representation of children in some coun- is a risk of patient misclassifi cation. This issue is par- tries. For this reason we restricted between-country ticularly important for CD, a widely variable disor- comparisons of CD prevalence to a well defi ned age der including cases with positive serology and normal range (30 – 64 years). 2) The occasional patient with histology (potential CD) (13) and cases with nega- IgA defi ciency and CD would have been missed by tive serology and positive histology (seronegative our IgA-based anti-tTG and EMA screening algo- CD) (44). Although the small-intestinal biopsy has rithm. 3) The MONICA materials from Germany an indisputable diagnostic role in the clinical setting, and the UK were collected earlier than other sera. this invasive investigation is not an essential require- This could infl uence our overall epidemiological ment for an epidemiological survey. As a matter of fi ndings reported in Table I, as it has been reported fact, in many recently published epidemiological that CD prevalence could change (increase) over studies the antibody positivity has been considered time (36,45). 4) The number of previously diag- as the only criterion for CD diagnosis (22 – 24). A nosed CD cases was identifi ed by questionnaires as a CD prevalence study based on serological screening part of the original health surveys. Since there could presents factors that could lead to slight over- or be an ascertainment bias in MONICA individuals under-estimation of CD prevalence. Since the sensi- investigated years before, we restricted the analy- tivity of serology is lower in patients showing a mod- sis of the diagnosed/undiagnosed ratio (celiac ice- est degree of intestinal damage (e.g. Marsh I lesion) berg) to the de novo investigated subjects (Table II). (44), serological screening may under-estimate the And 5) the ratio between anti-tTG and EMA ‘ true ’ prevalence. On the other hand, there are positivity was around 1.5 in most national samples, 594 K. Mustalahti et al. suggesting the possible ‘ false ’ positivity of low-titer Pathology, Universit à Politecnica delle Marche, anti-tTG. However in the German material collected Ancona, Italy, Zentrum M ü nchen, German in 1989 – 1990 the number of anti-tTG-positive Research Center for Environmental Health, Institute sera was ten times higher than EMA (Table I), for rea- of Epidemiology, Germany sons that remain unclear. We hypothesize that these old German samples underwent dehydration during Declaration of interest: The authors report no storage affecting the tTG quantitative determination confl icts of interest. The authors alone are respon- but not the semi-quantitative EMA test performed by sible for the content and writing of the paper. indirect immunofl uorescence. 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Journal

Annals of Medicine – Taylor & Francis

Published: Dec 1, 2010

Keywords: Anti-transglutaminase antibodies; celiac disease; epidemiology; population-based screening; prevalence

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