Determination of IgG and IgA Antibodies Against Native Gliadin
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Transcript of Determination of IgG and IgA Antibodies Against Native Gliadin
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8/13/2019 Determination of IgG and IgA Antibodies Against Native Gliadin
1/18Copyright ESPGHAN and NASPGHAN All rights reserved
Richter et al: Antibodies in celiac diagnosis in children aged up to two years
1
JPGN Journal of Pediatric Gastroenterology and Nutrition Publish Ahead of Print
DOI: 10.1097/MPG.0b013e31824678fc
Determination of IgG and IgA antibodies against native gliadin
is not helpful for the diagnosis of coeliac disease
in children up to 2 years of age
Thomas Richter1, Xavier Bossuyt
2, Pieter Vermeersch
2, Holm H. Uhlig
3, Martin Stern
4, Al-
muthe Hauer5, Klaus-Peter Zimmer
6, Luisa Mearin
7, Johanna Hendrika Clementina de Roo
7,
Cornelia Dhnrich8, and Thomas Mothes
9
From the 1 Childrens Hospital of the Clinical Centre Sankt Georg Leipzig, Germany, 2
Dept. Laboratory Medicine of University Hospital Leuven, Belgium,3University Childrens
Hospital Leipzig, Germany,4University Childrens Hospital Tbingen, Germany,
5Univer-
sity Childrens Hospital Graz, Austria,6
University Childrens Hospital Gieen, Germany,7
Department of Paediatrics, Leiden University Medical Centre, The Netherlands, 8
EUROIMMUN Medizinische Labordiagnostika GmbH Lbeck, Germany,9Institute of Labo-
ratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig,
Germany
Address for correspondence: Professor Dr. Thomas Mothes, Department of Laboratory Medi-
cine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Liebigstrae 27,
D-04103 Leipzig, Germany (e-mail: [email protected])
T. Mothes, H. H. Uhlig, and C. Dhnrich submitted patents on methods for CD diagnosis (T.
Mothes, A. Osman, H. H. Uhlig, T. Gnnel, A. Dietl: Peptide und Verfahren zur
Diagnostik von Zliakie und Dermatitis herpetiformis and C. Probst, C. Dhnrich, W.
Schlumberger, W. Stcker, L. Komorowski, T. Mothes: Verfahren und Immunabsorbentien
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Richter et al: Antibodies in celiac diagnosis in children aged up to two years
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zur spezifischen Detektion und Absorption Zliakie- und Dermatitis herpetiformis assoziierter
Antikrper). H. H. Uhlig was supported by the German Coeliac Society.
Key Words:antibodies, coeliac disease, deamidated gliadin, diagnosis, tissue transglutami-
nase
Abbreviations: AUC area under curve, CD coeliac disease, anti-dGli antibodies against
deamidated gliadin, anti-nGli antibodies against native gliadin, anti-tTG antibodies against
tissue transglutaminase, DOR diagnostic odds ratio, EmA endomysium antibodies, GFD glu-
ten-free diet; NLR negative likelihood ratio, PLR positive likelihood ratio, ROC receiver-
operating characteristics
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Richter et al: Antibodies in celiac diagnosis in children aged up to two years
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ABSTRACT
Objective:Assays for antibodies against native gliadin (anti-nGli) are still often assumed to
perform better in the diagnosis of coeliac disease (CD) in young children than tests for anti-
bodies to deamidated gliadin (anti-dGli), tissue transglutaminase (anti-tTG) and endomysium
(EmA). We compared the performance of assays for anti-nGli, anti-dGli, anti-tTG and EmA
in this age group.
Methods: We investigated retrospectively 184 children (42 coeliacs under normal diet and
142 controls) up to 2 years of age. IgA and IgG-anti-dGli, IgA and IgG-anti-nGli, IgA and
IgG-anti-tTG, and IgA-EmA were measured in serum. Areas under receiver-operating charac-
teristics curves (AUCs), sensitivities, specificities, positive (PPV) and negative predictive
values (NPV), positive and negative likelihood ratios (PLR and NLR), as well as diagnostic
odds ratios (DOR) were calculated.
Results: From all tests investigated, only assays for IgG-anti-dGli, IgA-anti-tTG and IgA-
EmA had high specificity (0.96) connected with high sensitivity (0.86), with high positive
predictive values (0.52 and 0.69 at pre-test probabilities of 0.05 and 0.1, respectively), and
with high negative predictive values (0.99 and 0.98 at pre-test probabilities of 0.05 and
0.1, respectively). These assays also showed high PLR (24) at low NLR (0.15) and high
DOR (136).
Conclusions: Our results do not support the use of assays of anti-nGli to diagnose CD in
young children. IgA-anti-tTG, IgA-EmA and IgG-anti-dGli perform better than anti-nGli.
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Assays for IgA antibodies against tissue transglutaminase (anti-tTG), endomysium (EmA) as
well as for IgG antibodies against deamidated gliadin peptides (anti-dGli) in serum have a
high sensitivity and specificity for coeliac disease (CD) in children (1,2). However, in young
children (up to two years of age), antibodies against native gliadin (anti-nGli) are still often
assumed to have the best performance. At young age, IgA-EmA have been reported to have a
low sensitivity (3-8), with maximum values of 89 %. The sensitivity of IgA-anti-tTG ranged
between 83 % and 90 % (1,6,8,9). Specificity of IgG-anti-nGli was only 77 % at high sensi-
tivity (5). IgA-anti-nGli were claimed to be best in finding CD in young children (6) with sen-
sitivity between 82 and 97 % and specificity between 88 and 94 % (1,5-8). The diagnostic
performance of anti-dGli in very young children still needs to be established. Recently, it was
shown that in children younger than 2 years with signs of chronic enteropathy and high serum
levels of anti-nGli, but normal values of anti-tTG and of EmA, CD can be predicted by high
serum levels of anti-dGli (10).
The aim of our study was to compare the diagnostic performance of assays for IgA and IgG-
anti-dGli, for IgA and IgG-anti-nGli, for IgA and IgG-anti-tTG, and for IgA-EmA in the di-
agnosis of CD at young age.
MATERIALS AND METHODS
Patients
Sera of 184 children below two years of age with and without CD were retrospectively inves-
tigated. The patients were recruited from the Childrens Hospital of the Clinical Centre Sankt
Georg Leipzig, (Germany), University Hospital Leuven (Belgium), University Childrens
Hospitals of Leipzig, Tbingen, Mnchen and Gieen (Germany), Childrens University
Hospital Graz (Austria), and from the Department of Paediatrics of the University Medical
Centre Leiden (The Netherlands). The patients comprised 42 children with CD and 142 con-
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trols (100 females and 84 males, mean age 1.34 years, range 0.4 to 2.0 years). Sera were
withdrawn at the time of the diagnostic duodenal biopsies. All patients were biopsied under
normal diet due to suspicion of CD or other gastrointestinal disorders. Intestinal pathology of
all CD patients was in accordance with Marsh 2 or Marsh 3 criteria (11,12). All CD patients
improved under gluten-free diet (GFD). The study was approved by the Ethical committee of
the University of Leipzig as well as of the local Ethical committees of the participating cen-
tres.
Antibody assays
IgA and IgG antibodies against deamidated gliadin analogous fusion peptides (anti-dGli),
anti-nGli, anti-tTG, and IgA-EmA were measured (blinded to the histological diagnosis) with
test kits from EUROIMMUN Medizinische Labordiagnostika Lbeck, Germany. EmA were
estimated by indirect immunofluorescence analysis using a combination of primate oesopha-
gus, primate small intestine, and primate liver. The analyses were performed by
EUROIMMUN. Cut-offs were as suggested by the manufacturer (Table 1).
Statistics
The data were evaluated by receiver operating characteristic (ROC) analysis. The area under
the ROC-curves (AUC) was calculated. Differences between ROC-curves were evaluated by
pairwise comparison according to Chi-Square analysis. An error probability P of less than
0.05 was considered statistically significant. Non-inferiority testing was performed if there
was no statistically significant difference. For non-inferiority testing, the lower end of 90 per
cent confidence intervals of differences between AUCs was considered. Non-inferiority was
assumed if the lower end of this confidence interval was not below a zone of diagnostic indif-
ference of 0.01.
For the cut-offs suggested by the manufacturer, diagnostic accuracies, sensitivities, and speci-
ficities were calculated. Significance of differences (P < 0.05) was evaluated applying
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McNemars test. For non-inferiority testing (see above), the proportions of children being
false-negative or false-positive were compared between two tests. The z-test was applied for
calculation of the 90 per cent confidence intervals of differences in proportions and for com-
parison of sensitivities and specificities in the different age groups.
RESULTS
From all tests investigated, only assays for IgG anti-dGli, IgA anti-tTG and IgA EmA had
high specificity (0.96) connected with high sensitivity (0.86), with high positive predic-
tive values (0.52 and 0.69 at pre-test probabilities of 0.05 and 0.1, respectively), and with
high negative predictive values (0.99 and 0.98 at pre-test probabilities of 0.05 and 0.1,
respectively, Table 1).
The IgG-anti-tTG assay showed the highest specificity (0.993). The specificity of the two
anti-dGli tests (0.972 and 0.965) was comparable with that of the assays for IgA-anti-tTG
(0.972) and IgA-EmA (0.958). The specificity of the IgG-anti-nGli test was significantly
lower than that of all other tests. The IgG-anti-tTG-test had a significantly higher specificity
than the IgA-anti-nGli assay. The 2 anti-dGli assays were non-inferior to the IgG-anti-nGli
test.
The IgG-anti-nGli test exhibited the highest sensitivity (0.929). The sensitivity of the IgG-
anti-dGli test (0.857) was as high as that of the IgA-anti-tTG and the IgA-EmA assay, and
higher than that of IgA-anti-dGli (0.810), IgA-anti-nGli (0.785), and IgG-anti-tTG (0.476)
assays. The low sensitivity of the latter test differed significantly from that of all other tests.
Positive likelihood ratios (PLR) were lowest for IgG-anti-nGli. These antibodies, however,
showed the also lowest negative likelihood ratio (NLR).
The diagnostic odds ratios (DOR) as an integrated measure of sensitivity and specificity were
lowest for IgA and IgG-anti-nGli (48.4 and 26.3, respectively) and highest for IgA-anti-tTG
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and IgG-anti-dGli (207 and 164, respectively).Similarly, ROC analysis revealed that from all
antibody tests examined, the AUCs of the IgA-anti-tTG and of the IgG-anti-dGli assay were
highest (0.951 and 0.950, respectively). Statistical evaluation of the ROC analysis showed
that the IgG-anti-dGli assay was non-inferior to that of IgA-anti-nGli, IgG-anti-nGli, IgG-
anti-tTG and IgA-EmA. The IgA-tTG assay was noninferior to the IgA-anti-dGli, the IgA-
anti-nGli and the IgA-EmA assay.
Mean concentrations of IgA and IgG-anti-dGli, of IgA-anti-tTG and of IgA-EmA were 50
fold higher in CD patients than in controls. Median concentrations were even increased at
least 200 fold. For IgA and IgG-anti-nGli and for IgG-anti-tTG, the factor of increase was
lower (Table 1).
Positive and negative predictive values of the tests in the children up to two years of age are
shown in Figure 1 as a function of pre-test probability. Positive predictive values of the anti-
dGli, anti-tTG, and EmA tests were higher (0.52 at a pre-test-probability of 0.05 and 0.69
at a pre-test probability of 0.1) than that of anti-nGli assays (0.37 at a pre-test probability of
0.05 and
0.55 at a pre-test probability of 0.1). The negative predictive value of the IgG-anti-
tTG test was lowest (0.97 at a pre-test probability of 0.05 and 0.94 at a pre-test probability of
0.1). Only IgA and IgG-anti-dGli, IgA-anti-tTG and IgA-EmA showed a high positive predic-
tive value in combination with a high negative predictive value.
In 19 (45 %) of our CD patients up to two years of age, all 7 antibody tests were positive (Ta-
ble 2). In 12 further CD patients (29 %) all but the IgG-anti-tTG antibodies were above the
cut-offs. In 3 of the CD patients antibody positivity was restricted only to IgG-anti-nGli anti-
bodies. In further 2 patients none of the tests was positive. There were 6 children (14 %) with
negative IgA-anti-tTG among the CD patients. Details of these patients are shown in Table 3.
In 89 (63 %) of the controls up to 2 years of age, none of the tests was positive (Table 2). In
further 35 controls (25 %) only the concentration of IgG-anti-nGli was elevated. In 3 controls
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(2 %), only IgA- and IgG-anti-nGli were positive. In 2 controls (1 %) IgA-anti-tTG together
with IgG-anti-nGli were elevated. In 2 further controls (1 %), all but IgA-anti-tTG and IgG-
anti-tTG were positive. In the remaining 11 controls, different combinations of antibody posi-
tivity were observed, which occurred only once. Altogether, there were 4 controls with in-
creased IgA-anti-tTG. In all of them, concentration of IgA-anti-tTG was higher than twofold
the cut-off. In 2 of them, also an elevated concentration of IgG-anti-dGli was found. In one of
these 2 controls, the antibody concentration could be controlled after 19 months (both anti-
bodies positive) and after 23 months (both antibodies negative).
DISCUSSION
Except for IgG-anti-nGli, the specificity of all antibody tests was high for CD for patients up
to 2 years. However, the assays with high specificity (IgA- and IgG-anti-dGli and anti-tTG,
IgA-anti-nGli and EmA) exhibited a low sensitivity, whereas the low specificity of the IgG-
anti-nGli test was associated with a high sensitivity. Using paired indicators of diagnostic
performance such as sensitivity and specificity or PLR and NLR can be a disadvantage in
comparing the performance of competing tests, especially if one test does not outperform the
other on both indicators. The DOR can be used as a single indicator of diagnostic
performance and combines the strengths of sensitivity and specificity as well as of PLR and
NLR and is independent on prevalence (13). Regarding the DOR, the performance of the IgA
and IgG anti-nGli was worst.
For further evaluation of the tests, calculation of predictive values at defined pre-test probabil-
ity is useful. In contrast to screening conditions with a prevalence of about 1 %, in paediatric
gastroenterology centres a higher pre-test probability has to be assumed. At a pre-test prob-
ability of CD of about 0.05, all tests except the assays for IgA- and IgG-anti-nGli result in
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post-test probabilities of at least 0.52 (Figure 1). The post-test probability of IgA- and IgG-
anti-nGli tests was below 0.4. A high positive predictive value reduces the number of patients
who need to undergo endoscopy. The negative predictive value is very high for all tests (
0.99) except for IgG-anti-tTG (0.97). A high negative predictive value assures that the num-
ber of CD patients among the children with negative test results is minimum (at most 1 %).
Thus, from all tests investigated, only assays for IgG anti-dGli, IgA anti-tTG and IgA EmA
had high specificity (0.96) connected with high sensitivity (0.86), with high positive pre-
dictive values (0.52 and 0.69 at pre-test probabilities of 0.05 and 0.1, respectively), and
with high negative predictive values (0.99 and 0.98 at pre-test probabilities of 0.05 and
0.1, respectively). Therefore, these assays should be preferred over tests measuring anti-nGli.
A selection bias in our study cannot be excluded. First of all, biopsies are more likely to be
performed in symptomatic patients with positive results for CD specific antibodies such as
IgA-EmA and IgA-anti-tTG, which favours these tests. Furthermore, most children in this
study had not been re-challenged with gluten in order to confirm the diagnosis of CD, which
wasrequired according to thepreviousESPGHAN criteria on the diagnosis of CD (14). Re-
cently, it was suggested that routine gluten challenge in patients below two years of age is not
necessary when patients have villous atrophy in combination with positive EmA (7). Accord-
ing to forthcoming ESPGHAN guidelines, a later gluten challenge should only be performed
if villous atrophy was found in children below to years of age, who are negative for CD spe-
cific antibodies in order to confirm CD as a cause of the enteropathy (15). Six of our patients
were classified as coeliacs in the absence of increased IgA-anti-tTG (however, one of them
positive for IgA-EmA and this patient and another positive for routine assay of IgA-anti-tTG
outside of this study). The latter finding shows that occasionally diverse results may be ob-
tained when tests of different suppliers are compared (16). In fact, none of the remaining four
patients was re-challenged with gluten until now, mainly due to their youngage. According to
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Conflicts of interest: T. Mothes, H. H. Uhlig, and C. Dhnrich submitted patents on methods
for CD diagnosis (T. Mothes, A. Osman, H. H. Uhlig, T. Gnnel, A. Dietl: Peptide und
Verfahren zur Diagnostik von Zliakie und Dermatitis herpetiformis and C. Probst, C.
Dhnrich, W. Schlumberger, W. Stcker, L. Komorowski, T. Mothes: Verfahren und
Immunabsorbentien zur spezifischen Detektion und Absorption Zliakie- und Dermatitis
herpetiformis assoziierter Antikrper).
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2. Prause C, Ritter M, Probst C, et al. Antibodies against deamidated gliadin as new and accu-
rate biomarkers of childhood coeliac disease.J Pediatr GastroenterolNutr2009b;49:52-8.
3. Brgin-Wolff A, Gaze H, Hadziselimovic F, et al. Antigliadin and antiendomysium anti-
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5. Tonutti E, Visentini D, Bizzaro N, et al. The role of antitissue transglutaminase assay for
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6. Lagerqvist C, Dahlbom I, Hansson T, et al. Antigliadin immunoglobulin A best in finding
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children with chronic diarrhoea.Dig Liver Dis 2011;43:465-469
11. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecu-
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12. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for
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13. Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PMM. The diagnostic odds ratio: a
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14. Walker-Smith JA, Guandalini S, Schmitz J, et al. Revised criteria for diagnosis of coeliac
disease. Report of Working Group of European Society of Paediatric Gastroenterology and
Nutrition.Arch Dis Child 1990;65:909-11.
15. Husby S, Koletzko S, Korponay-Szab IR, et al. ESPGHAN guidelines for the diagnosis
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16. van Meensel B, Hiele M, Hoffman I, et al. Diagnostic accuracy of ten second-generation
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FIGURE LEGENDS
FIGURE 1. Predictive values of the different antibody assays in the diagnosis of CD in children up to
two years of age in dependence on pre-test probability.The thick grey line in the lower diagram collec-
tively indicates negative predictive values of IgG-anti-dGli, IgA-anti-tTG as well as IgA-EmA, which
are very similar. The vertical dotted line indicates a pre-test probability of 0.05.
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Table 1
TABLE 1. Performance of different antibody tests in children aged up to 2 years
IgA-anti-dGli
IgG-anti-dGli
IgA-anti-nGli
IgG-anti-nGli
IgA-anti-tTG
IgG-anti-tTG
IgA-EmA*
Test-No. 1 2 3 4 5 6 7
Cut-off (U/L) 25.0 25.0 25.0 25.0 20.0 1.0 10
AUC 0.936 0.9503,4,6,7 0.920 0.931 0.9511,3,7 0.912 0.925
Specificity 0.97234 0.9653
4 0.930
4,6 0.669
1,2,3,5,6,70.972
4 0.993
3,45 0.958
4
Sensitivity 0.8106 0.857
6 0.786
4,6 0.9291
3,6 0.857
6 0.476
1,2,3,4,5,7 0.857
3,6
PLR 28.7 24.3 11.2 2.81 30.4 67.6 20.3
NLR 0.196 0.148 0.231 0.107 0.147 0.528 0.149
DOR 147 164 48.4 26.3 207 128 136
95 % CI 41.7 to 515 47.5 to 569 18.2 to 129 7.72 to 89.5 55.5 to 773 16.4 to 1004 41.4 to 447
AbC CD (U/L)
Mean 437 296 252 241 427 1.13 773
Median; range 580; 0.4-711 286; 0.8-700 200; 1.0-551 200; 3.3-520 457; 0.5-700 0.0-5.5 320; 0-10000
AbC Co (U/L)
Mean 3.46 5.62 9.01 35.73 3.40 0.09 1.06
Median; range 1.0; 0.0-94.3 1.4; 0.2-173 1.5; 0.3-191 10.0; 0.6-220 0.74; 0.0-98.5 0.04; 0.00-1.37 0; 0-100
* For EmA the reciprocal values of the titres are presented. CI: Confidence interval; AbC CD: Antibody concentration in CD
patients; AbC Co: Antibody concentration in control patients. Superscripts denote significant differences to tests with therespective numbers. Subscripts denote non-inferiority to the tests with the respective numbers. Results of non-inferiority tests
only shown if there was no statistically significant difference.
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Table 2
TABLE 2.Antibody profiles in CD patients and controls aged up to 2 years
IgA-anti-dGli
IgG-anti-
dGli
IgA-anti-
nGli
IgG-anti-
nGli
IgA-anti-tTG
IgG-anti-tTG
IgA-EmA
Number ofpatients
CD + + + + + + + 19
+ + + + + - + 12
- - - + - - - 3
- - - - - - - 2
Con-
trols- - - - - - - 89
- - - + - - - 35
- - + + - - - 3
- - - + + - - 2
+ + + + - - + 2
For sake of clarity, from the total of 184 patients, profiles are only shown if occurring more than in one patient. Six CD pa-
tients and 11 control patients had unique antibody profiles.
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Table 3
TABLE 3. Patients with negative IgA-anti-tTG classified as CD
No Total IgA HLA Histology IEL Other positive
antibodies
Further findings
1 sIgAD DQ8 Marsh 3A >40 IgG-anti-nGli Routine test of IgAanti-tTG negative
2 Normal n.d. Marsh 2 >40 None IgA-anti-tTG, IgA-EmA, IgA- and IgG-anti-dGli
positive 64 days before endoscopy. Preterm GFD?
3 Normal n.d. Marsh 3C >40 None Routine test of IgA-anti-tTG negative
4 Normal n.d. Marsh 3C >40 IgG-anti-nGli Routine tests of IgA-anti-tTG and IgA-EmA
positive. Progressive decrease in total IgA during
follow up
5 Normal DQ2 Marsh 3B >40 IgG-anti-nGli Routine test of IgA-anti-tTG negative
6 Unknown n.d. Marsh 3A >40 IgA-anti-nGli
IgG-anti-nGli
IgG-anti-dGli
IgA-EmA
Routine tests of IgA-anti-tTGand IgA-EmA positive
None of the patients was re-challenged with gluten. sIgAD: secretory IgA-deficiency. n.d.: not determined.Routine tests: performed in clinical routine at the time of endoscopy outside of this study.Lack of IgA improbable since IgA-anti-nGli and IgA-EmA increased.