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Original Articles: Gastroenterology: Celiac Disease

Will the Real Coeliac Disease Please Stand Up? Coeliac Disease Prevalence in the German LIFE Child Study

Händel, Norman; Mothes, Thomas; Petroff, David; Baber, Ronny†,§; Jurkutat, Anne§; Flemming, Gunter; Kiess, Wieland∗,§; Hiemisch, Andreas∗,§; Körner, Antje∗,§; Schlumberger, Wolfgang||; Thiery, Joachim†,§; Wolf, Johannes

Author Information
Journal of Pediatric Gastroenterology and Nutrition: October 2018 - Volume 67 - Issue 4 - p 494-500
doi: 10.1097/MPG.0000000000002052

Abstract

What Is Known

  • Prevalence of coeliac disease in Germany is lower compared to other European countries
  • Immunoglobulin A against tissue transglutaminase possesses high sensitivity but low positive predictive values under screening situations.
  • Nonrecurring, uncombined antibody measurements at randomly selected time points and missing human leukocyte antigen-DQ status may lead to overestimation of the “true” coeliac disease prevalence.

What Is New

  • German seroprevalence and prevalence of definite coeliac disease are higher than previously described.
  • IgG antibodies against deamidated gliadin peptides are not suitable for screening.
  • Children and adolescents with immunoglobulin A against tissue transglutaminase levels between 0.5 and 1 × upper limit of normal should be investigated prospectively.

Coeliac disease (CD) is an autoimmune-mediated enteropathy triggered by gluten peptides from wheat and related cereals in genetically predisposed patients (1). With the growing awareness of CD among healthcare professionals and the emergence of reliable screening tools, more children are found with oligo- or even asymptomatic disease course rather than children with classic signs of malabsorption (2–4). Although comparative studies from non-representative cohorts provide some evidence, it has not been clarified in detail whether asymptomatic patients with CD under gluten-containing diet are at risk for increased morbidity and mortality in general (5,6).

The worldwide CD prevalence is reportedly between 0.18% and 2.38% (7,8) depending on the size and mean age of the screened population as well as the serological tests used.

Four German studies are available which screened paediatric and/or adult cohorts applying different strategies (8–11). The prevalence of biopsy-proven CD was found to be between 0.18% and 0.37% (8,9). This is lower than in other European countries (0.5%–2.5%) (7,12,13). Contrary to the above estimates, seroprevalence in randomly selected German cohorts was between 0.8% and 1.35% (10,11). The difference between prevalence of biopsy-proven CD and seroprevalence may be due to a lower specificity of the antibody tests in an unselected population. A recent screening study (14) demonstrated that 98% of the participants with immunoglobulin A (IgA) anti-tissue transglutaminase (IgA-TTG) values ≥10 times of upper limit of normal (ULN) exhibit mucosal impairment compatible with CD (≥Marsh 3A).

The primary objective of our study was to estimate the prevalence of CD in a German paediatric cohort applying IgA-TTG measurement, additional confirmatory antibody tests, and human leukocyte antigen (HLA) genotyping. From participants with suspicious blood test results, antibody testing was repeated about 1 year later. We address the question whether antibody test results alone can predict the true prevalence of CD in a screening cohort.

METHODS

LIFE Child

LIFE Child (clinical trial number NCT02550236) is a prospective, population-based longitudinal cohort study conducted at the Leipzig Research Center for Civilization Diseases (LIFE) in Leipzig, a city in central Germany with >500,000 inhabitants (15). The LIFE study is designed to understand how genetic, metabolic, and environmental factors influence the health and development of children and adolescents (15–17). LIFE Child is a study of urban children from foetal life to adulthood. The study focuses on monitoring of growth, development, and health. Study participants are recruited via advertisement at hospitals, public health centres, and schools, by different media or by word of mouth. LIFE Child consists of 3 interrelated cohorts: birth, health, and obesity cohorts (15).

Ethics Statement

The study was designed in accordance with the declaration of Helsinki and under supervision of the local ethics committee (reg. no. 264-10-19042010). Informed consent is obtained from all individual participants and/or their guardians included in the study. In case of relevant incidental findings, these are reported to the families as well as their primary care physicians (18).

Study Population

From April 2011 to November 2015, 3080 children and adolescents were enrolled in LIFE Child Health. Venous blood was taken in the morning. The samples were processed by the LIFE preanalytical laboratory and stored in the LIFE biobank. We only included subjects aged between 1 and 18 years of whom at least 2 biobanked serum aliquots were available (premise of the LIFE management) from the first LIFE Child visit. In total, 2363 participants (49% girls and 51% boys with mean age of 8.48 years, SD 4.62) were screened.

Questioning and Anthropometric Data

Children and their parents participating in LIFE Child underwent interviews, medical examinations, standardised tests, questionnaires, and the collection of biological samples. Information on children's diseases was reported by parents in a computer-assisted personal interview. Weight and height were determined in standardised ways (15,16).

Laboratory Assays

For detection of IgA-TTG and IgG antibodies against deamidated gliadin peptides (IgG-DGP), ELISAs of EUROIMMUN (Lübeck, Germany) were applied (cut-off ≥20 and ≥25 U/mL, respectively). IgA antibodies against endomysium (IgA-EmA, cut-off ≥1:10) were assessed by indirect immunofluorescence analysis using primate liver sections (19) provided by EUROIMMUN. For HLA genotyping, the EUROArray HLA-DQ2/DQ8 kit of EUROIMMUN was applied. Total IgA was measured nephelometrically with test kits of Roche (Mannheim, Germany).

Antibodies were assayed as single measurement. IgA-TTG results >0.5 × ULN and IgG-DGP results ≥1 × ULN were confirmed by a further single measurement. If concentrations were above the measurement range, sera were serially diluted and assay results corrected by the dilution factor.

Baseline Screening (T0)

The initial screening comprised determination of IgA-TTG and IgG-DGP. In addition, sera with IgA-TTG values >0.5 × ULN and positivity of IgG-DGP were tested for IgA-EMA and if available, DNA samples were analysed for HLA-DQ2.2, -DQ2.5, and -DQ8. Both, IgA-EmA and HLA were tested without knowledge of the ELISA results. In sera solely positive for IgG-DGP total IgA was measured. IgA values of ≤0.05 g/L defined selective IgA deficiency (sIgAD). In addition, for participants who claimed to have CD, HLA genotyping was performed.

First Follow-up (T1)

Follow-up sera of patients with conspicuous results from baseline screening (IgA-TTG ≥0.5 × ULN and/or positive IgG-DGP with HLA-DQ2 and/or -DQ8 positivity or unknown HLA status) were analysed for IgA-TTG and IgA-EmA usually 12 months after initial baseline screening.

Second Follow-up (T2)

We invited participants for a personal interview (T2a) who were either positive for IgA-TTG at T0 and/or T1 or had IgA-TTG >0.5 × ULN at T0 and increased concentration of IgA-TTG at T1 or positive IgG-DGP at T0 and T1 or those with positive IgG-DGP at T0 and a missing T1 sample. Participants with known CD were not invited and cases with negative results for HLA-DQ2 or -DQ8 were excluded. The questionnaire comprised data concerning gastrointestinal complaints, further CD-related symptoms, associated diseases, family history, and gluten-consumption. Due to the restrictions of the LIFE Child study protocol, we were not allowed to perform additional diagnostic sampling (blood or biopsy) inside the framework of LIFE Child. Therefore, we informed the general practitioner (GP) or the paediatrician routinely taking care of the patient about the study data (T2b). After about 6 months, participants who consented to be contacted again were consulted regarding antibody test results, endoscopic findings, and, in particular, in terms of CD diagnosis. Finally, all available patient's data were compiled to make a final diagnosis.

Definition of Seropositivity, Suspected Coeliac Disease, Definite Coeliac Disease, and Non-Coeliac Disease

CD seropositivity was defined to be IgA-TTG and/or IgA-EmA positivity or if IgG-DGP positivity with total IgA ≤0.05 g/L on at least 1 LIFE child visit irrespective of the HLA genotype.

Suspected CD was defined as seropositivity and HLA-DQ2/DQ8 positivity with hitherto unproven mucosal damage. If HLA genotype was not available, positive IgA-TTG with additional IgA-EmA positivity was also considered as suspected CD.

Definite CD was regarded if there was seropositivity on at least 1 visit (LIFE Child or 1 further visit at GP and/or gastroenterologist) and a positive intestinal biopsy (≥Marsh 2) was found or if IgA-TTG ≥10 × ULN (15) on at least 1 visit without biopsy results.

We used the term non-CD if IgA-TTG was <0.5 × ULN at T0, or if in baseline screening initially increased IgA-TTG was reported by the GP or the paediatric gastroenterologist to be decreased below the cut-off under gluten-containing diet, or if IgA-TTG was 0.5 to 1.0 × ULN at T0 and T1 without further clarification at GP or gastroenterologist, or the histology was inconsistent with CD (≤Marsh 1). All other subjects were classified as unclear.

Statistical Analysis

Data handling and statistical analysis were performed with the software package R version 3.4.1. Data were analysed descriptively with regard to absolute and relative frequencies, arithmetic means and standard deviation. Frequencies such as prevalence were estimated along with 95% Wilson confidence intervals (CI95%) (20). We compared count data using the χ2-test. P values ≤0.05 were considered significant.

RESULTS

A flow-chart showing the number of participants at each stage of the study is provided in Figure 1.

F1
FIGURE 1:
Schematic flow chart of studied children and adolescents in LIFE Child Health. Numbers of participants at each screening step are given. Subjects with IgA-TTG lower than 0.5 × ULN for IgA-TTG and with negative IgG-DGP or negative HLA-DQ2/8. CD = coeliac disease; GP = general practitioner; IgG-DGP = immunoglobulin G against deamidated gliadin peptides; IgA-TTG = immunoglobulin A against tissue transglutaminase; PG = paediatric gastroenterologist; ULN = upper limit of normal.

Results of Baseline Screening (T0)

Screening results for IgA-TTG and IgG-DGP with results from subsequent tests (IgA-EmA, and HLA genotyping) are shown in Figure 2A and B. Of 2363 children, 29 were positive for IgA-TTG (1.23%, CI95% 0.86–1.76). From the 2334 IgA-TTG negative children, 23 were solely positive for IgG-DGP (0.99%, CI95% 0.66–1.47), none of whom had positive IgA-EmA.

F2
FIGURE 2:
Results of baseline screening (T0). (A) IgG-DGP, IgA-EmA and HLA in children with positive IgA-TTG. From all 2363 children, 29 were positive for IgA-TTG. (B) IgG-DGP, IgA-EmA and HLA in children with negative IgA-TTG. From 2334 IgA-TTG negative children, 23 were positive for IgG-DGP. Numbers in bold were selected for the first follow-up (n = 47). One child with known CD. #One child with selective IgA deficiency (total IgA ≤0.05 g/l). CD = coeliac disease; HLA = human leukocyte antigen; IgG-DGP = immunoglobulin G against deamidated gliadin peptides; IgA-EmA = IgA antibodies against endomysium; IgA-TTG = immunoglobulin A against tissue transglutaminase; N/A = not known.

Nine children were positive for IgA-TTG and for IgG-DGP (0.38%, CI95% 0.20–0.72). All 8 participants with IgA-TTG ≥10 × ULN (0.34%, CI95% 0.17–0.67) were also positive for IgA-EmA. From the 21 children with IgA-TTG between 1 and 10 × ULN, only 14 had positive IgA-EmA. Interestingly, 2 of the 15 children with IgA-TTG between 0.5 and 1 × ULN show IgA-EmA positivity.

All IgA-EmA positive participants had a CD compatible HLA genotype (HLA-DQ2 and/or DQ8). Otherwise, children with positive IgA-TTG but negative IgA-EmA were found to be only positive for HLA-DQ2 and/or DQ8 in 4 of 7 cases (57.1%). Participants with positive IgG-DGP but negative IgA-TTG and negative IgA-EmA had a CD compatible HLA genotype in only 11 of 23 cases. One of them was a child with sIgAD.

Patients With Already Known Diagnosis of Coeliac Disease

In 7 of 2363 cases, it was claimed that CD has been previously diagnosed (0.30%, CI95% 0.14–0.61). One child had HLA-DQ2.5 and was still positive for IgA-TTG (4.45 × ULN) and IgA-EmA (1:320) at T0. The antibody concentration decreased within 1 year to 0.8 × ULN and 1:10, respectively, suggesting adherence to gluten-free diet. Remarkably, only 3 of the remaining 6 children were HLA-DQ2 and/or -DQ8 positive.

First Follow-up (T1)

We obtained sera from 33 of 47 children with conspicuous test results at baseline screening for first follow-up (Fig. 3). Of these 33 children, 16 had positive baseline IgA-TTG (groups 1–3), 12 of which remained positive, 1 even increased by more than a factor of 2, but 7 decreased by more than a factor of 2. In group 4 (initial IgA-TTG levels 0.5–1 × ULN) IgA-TTG increased above the cut-off in 5 of 10 participants, increased by more than a factor of 2 in 3 of these and decreased by at least a factor of 2 in 2 subjects. None of the 7 children of group 5 (initial IgA-TTG <0.5 × ULN but positive IgG-DGP) developed positive IgA-TTG or IgA-EmA at follow-up, though values increased by more than a factor of 2 for 2 of them. For further details see Supplementary Table 1 and Supplementary Figure 1 (Supplemental Digital Content 1 and 2, https://links.lww.com/MPG/B401, https://links.lww.com/MPG/B402).

F3
FIGURE 3:
Results of screening at first follow-up (T1). For explanation of groups see Fig. 2. Eighteen children in groups 3, 4, and 5 without genetic CD compatibility were not considered for the first follow-up. Criteria for follow-up at T1 are IgA-TTG ≥ 0.5 × ULN and/or positive IgG-DGP with HLA-DQ2 and/or -DQ8 positivity or unknown HLA status. §One patient with already known diagnosis of CD. #One patient with positive IgG-DGP at T0, increase of IgG-DGP and IgA-TTG (7–16 U/mL at a cut-off of 20 U/mL) at T1, 2× positive IgA-TTG at GP. CD = coeliac disease; HLA = human leukocyte antigen; GP = general practitioner; IgG-DGP = immunoglobulin G against deamidated gliadin peptides; IgA-TTG = immunoglobulin A against tissue transglutaminase; ULN = upper limit of normal.

Prevalence of Seropositivity and Suspected Coeliac Disease

The proportion of seropositivity was 1.57% (CI95% 1.14–2.15). The prevalence of suspected CD was 1.35% (CI95% 0.96–1.91), without special consideration of participants who claimed to have CD. There was no indication that subjects with and without seropositivity, and with suspected CD differed in any meaningful way in age, gender distribution, and anthropometric data.

Second Follow-up and Prevalence of Coeliac Disease

We invited 39 participants (30 with positive IgA-TTG, 8 with solely positive IgG-DGP, and 1 with initial IgA-TTG ≥0.5 × ULN, which was further increased at the first follow-up) for a personal interview of whom 34 children took part. Data on antibody values, HLA genotype, clinical status, associated disorders in the family, and histology for these children are given in Supplementary Table 1 and Supplementary Figure 1 (Supplemental Digital Content 1 and 2, https://links.lww.com/MPG/B401, https://links.lww.com/MPG/B402).

Fifteen participants were asymptomatic. A significantly higher proportion of symptomatic in comparison to asymptomatic subjects (73.7% vs 33.3%, P = 0.019) presented to a GP or paediatric gastroenterologist for further clarification.

Ten of the 39 participants were assigned to the category definite CD. In 16 cases CD was excluded. The remaining 13 cases were classified as unclear (Supplementary Table 1 and Supplementary Figure 1, Supplemental Digital Content 1 and 2, https://links.lww.com/MPG/B401, https://links.lww.com/MPG/B402). Thus, the prevalence of definite CD in our cohort was 0.42% (CI95% 0.23–0.78). Interestingly, we found no differences between seropositive patients and the remainder in Table 1 except for mean corpuscular volume and thyroid stimulating hormone. If we add the 4 patients with already known CD and compatible HLA genotype, an overall prevalence of at least 0.59% (CI95% 0.35–0.99) is obtained.

T1
TABLE 1:
Baseline demographics and laboratory parameters

Unclear Cases

Thirteen of 39 subjects were assigned to the group of unclear cases. Only 1 visited the GP or paediatric gastroenterologist. Despite strong suspicion of CD, 5 of 13 unclear cases refused further clinical investigations after the personal interview, mainly due to lacking symptoms.

DISCUSSION

The current study in the LIFE Child Health cohort is a prospective, population-based CD screening including follow-up of suspicious subjects and applying 3 different antibody tests as well as HLA genotyping. The proportion of seropositive children in our study is higher (1.57% vs 0.8%) than in the most recent German CD prevalence study (11) and exceeds the seroprevalence of the most recent screening studies from Europe, New Zealand, and Iran (7,8). Metzger et al found a very similar 1.35% with positive IgA-TTG antibodies in an adult cohort (10).

As expected, the prevalence of suspected CD with so far unknown mucosal damage was lower in comparison to seropositivity (1.32% vs 1.57%). The related term potential CD usually describes individuals with a normal (or unknown) duodenal mucosa architecture who are at increased risk of developing CD (eg, positive HLA-DQ2 and/or DQ8) as indicated by positive CD serology (21). The patients may or may not have symptoms and signs of the disease and may or may not develop a gluten-dependent enteropathy later on (22). Our large prospective antibody study demonstrated that those with positive IgA-EmA and IgA-TTG were also HLA-DQ2 and/or DQ8 positive (23). Therefore, we assumed for our screening situation that all cases with IgA-TTG and IgA-EmA positivity lacking HLA-DQ typing are HLA-DQ2 and/or DQ8 positive and therefore could be assigned to the group of what we termed suspected CD. Otherwise, participants with IgA-TTG between 1 and 10 × ULN but with negative IgA-EmA were positive for HLA-DQ2/8 in only 4 of 7 cases.

The proportion of children with definite CD in our study was 0.42%. In addition to the patients with biopsy-confirmed CD, participants with IgA-TTG levels ≥10 × ULN are very likely to have CD even in the screening situation (14). It was shown that IgA-TTG levels ≥10 × ULN predict mucosal damage ≥Marsh 3A in a population based-screening independent of the patient's symptomatic state. Furthermore, we have recently shown that a positive predictive value for IgA-TTG concentration ≥10 × ULN remains high even at very low prevalence and irrespective of underlying symptoms (23). Therefore, those subjects were assigned the category definite CD even without biopsy. The proportion of participants with IgA-TTG ≥10 × ULN (0.34%) was the same in comparison to a recent evaluation in Germany (11) but lower than in studies from Sweden (14,24); however, the diagnostic properties of the tests used should be taken into account. The frequency of participants with IgA-TTG >10 × ULN even exceeds the estimated German prevalence for children with biopsy-proven CD (9).

For a lower limit on the overall prevalence of CD we include those patients with already known CD and appropriate HLA genotype. Hereby, we obtain an overall prevalence of 0.59%. Notably, of 7 participants who claimed to be previously diagnosed as CD patient, only 4 were HLA-DQ2 and/or DQ8 positive. We conclude that inclusion of subjects who say they have CD into the calculation of prevalence without HLA genotyping leads to an overestimation of the frequency. Furthermore, the overall prevalence of CD of those who returned for further evaluation reached only about one-third of the seropositive participants indicating a possible low performance of IgA-TTG in the screening situation. Even with an extremely high specificity of 99.5% and a CD prevalence of 1%, the positive predictive value in a screening situation would be below 70%. This was confirmed by our data. Unfortunately, a substantial proportion of subjects with suspected CD did not wish further clarification or were unattainable. Taking into account that some of those who did not return for follow-up most likely have CD and that at least 15% to 30% of the unclear cases with suspected CD will develop CD later in life (25,26), the prevalence of CD in LIFE child is likely to be above 0.8%. A further limitation is that one cannot be certain that the cohort was representative of a paediatric German population.

A major strength of this study is that we repeated the antibody testing after about 1 year for children with suspicious antibody results. This allowed the identification of participants with transient elevation of antibody concentration. In total, we found 3 HLA-positive children who had a positive baseline and a clearly negative IgA-TTG result at first follow-up (see supplementary Table 1, Supplementary Digital Content 1, https://links.lww.com/MPG/B401, cases 23–25). Otherwise, we observed seroconversion of IgA-TTG from negative to positive for 5 of 10 participants with initial IgA-TTG levels between 0.5 and 1 × ULN. One was also positive for IgG-DGP. Regarding these results, there is evidence that a fraction of the subjects with suspected CD should be followed up if initial IgA-TTG values are between 0.5 and 1 × ULN. A birth-cohort screening (27) of children with a genetic risk to CD showed similar results whereas predisposed children were screened at 3 and 9 years of age.

The value of IgG-DGP as an additional test in addition to its use to detect patients with IgA-deficiency for diagnosis of CD is still debatable (28,29). Here, we examined its possible potential as a screening test. We found a false-positive rate of about 50% (lacking HLA-DQ2 and/or DQ8) for those samples with solely IgG-DGP positivity indicating the necessity for HLA genotyping in these cases. This supports the recommendation to genotype IgA-TTG seronegative patients with CD-related signs (30) to evaluate the need of subsequent endoscopic evaluation. In case of HLA-DQ2/8 negativity CD seems to be very unlikely and other differential diagnoses have to be considered. We did find 1 girl with sIgAD carrying HLA-DQ2.5 by IgG-DGP. Furthermore, 1 boy with isolated IgG-DGP positivity and HLA-DQ2.5 developed IgA-TTG seropositivity after the first follow-up which was confirmed by the GP (Supplementary Figure 2, Supplemental Digital Content 3, https://links.lww.com/MPG/B403). Unexpectedly, the girl had no mucosal changes and the boy showed only a crypt hyperplasia without elevated intraepithelial lymphocytes. In both cases CD has not been diagnosed, but both will be followed up.

To conclude, our findings show an overall prevalence of CD of at least 0.59% and likely higher, which is somewhat lower than the prevalence reported in other European studies but higher than previously described for Germany. Our findings suggest that a positive IgA-TTG test result should be complemented by EmA-testing. In case of EmA-negativity, HLA genotyping is helpful. The follow-up of children with initial IgA-TTG test results between 0.5 and 1 × ULN reveals few special cases with positive seroconversion. In none of them CD could, however, be finally diagnosed until the end of our study. Under our screening conditions, assay of IgG-DGP did not unravel additional CD patients. HLA genotyping is useful in case of IgA-TTG positivity combined with EmA negativity and can unmask cases of misdiagnosis.

Acknowledgments

The authors thank EUROIMMUN AG (Conny Daehnrich, Annika Jahnke, Kathrin Axel, and Ulf Steller) for providing the ELISA kits and analysing EmA and HLA-DQ2/Q8. The authors are deeply grateful to all the families who have taken part in the LIFE study, and the whole LIFE Child team.

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Keywords:

deamidated gliadin; endomysium antibodies; human leukocyte antigen; potential coeliac disease; screening; seropositivity; tissue transglutaminase

Supplemental Digital Content

Copyright © 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition