Clinical course of new-onset Crohn's disease in children and adolescents in dependency of age, initial location, initial severity level and therapy over the period 2000-2014 based on the Saxon Pediatric IBD-Registry in Germany.

OBJECTIVE: In Saxony, the incidence of Crohn's disease (CD) in children and adolescents increased significantly from 3.3 per 100,000 person-years in 2000 to 5.1 in 2014. The aim of this study was to describe the initial characteristics and the clinical course of CD in children and adolescents and to identify drug treatment options associated with an advantage for a mild course or remission. METHODS: Clinical data were collected from patients who suffered from inflammatory bowel disease (IBD) and were recruited in the Saxon Pediatric IBD-Registry. All children newly diagnosed with CD in this registry in Saxony between 2000 and 2014 were included in this registry study. Characteristics such as age, disease location and extra-intestinal manifestations at diagnosis were accessed. The severity level of the disease at diagnosis as well as at follow-up were analysed by PCDAI index. Patients were divided into 3 groups according to length of follow-up: 1-3 years, 4-6 years and 7-9 years after diagnosis. A logistic regression model was conducted to examine which baseline parameters are associated with disease progression. RESULTS: There were 338 children and adolescents with CD included in this registry study. At diagnosis, the median age of patients was 12.0 (0.7-14.9), 61.5% (n = 208) of the patients were male. The most common disease location observed in pediatric CD patients was the L3 (55%, n = 176). Patients aged 10-14 years were significantly more likely to present an L2 than patients aged 0-4 years (80.3%, n = 53 vs. 19.7%, n = 13, p = 0.01). During the follow-up, data from 71.3% (n = 241) othe patients were available. Disease activity measured by PCDAI decreased in 47.7% (n = 115) of the patients, 40.7% (n = 98) of the patients were stable and increased in 11.6% (n = 28) of the patients. Patients with intermediate/severe disease at onset were more likely to have an active disease at the end of follow up, too (p = 0.00). Logistic regression analysis of the initial characteristics showed that the age at diagnosis, gender, initial location and initial extra-intestinal manifestation are not associated with the progression of the disease (p>0.05). Furthermore, drug treatment options could be identified from our data, which are associated with benefits for a milder course or remission. CONCLUSION: From 2000 to 2014, the health status of most pediatric patients with CD had improved or remained stable. Initial characteristics including age at diagnosis, initial localization and initial extra-intestinal manifestation are not associated with the progression of the disease, only the initial activity by PCDAI.

Pediatric percentiles for transient elastography measurements - effects of age, sex, weight status and pubertal stage.

Background and aims: Transient Elastography is a non-invasive, cost-efficient, non-ionizing, observer-independent and reliable method to detect liver fibrosis using Liver Stiffness Measurement (LSM) and the degree of fat accumulation in the liver using Controlled Attenuation Parameter (CAP). This study aims to derive reference values for both measures from healthy children and adolescents. Further, we aim to assess the potential influence of age, sex, puberty, and BMI-SDS on CAP and LSM. Methods: Within the LIFE Child study, amongst others, anthropometric data and pubertal status were assessed. Transient Elastography (TE) was performed using the FibroScan® device in a population-based cohort at 982 study visits of 482 healthy children aged between 10 and 18 years. Percentiles for LSM and CAP were estimated, and the effects of age, sex, puberty and weight status were assessed through hierarchical regression models. Results: There was a strong age dependency for LSM with higher values for older children, most pronounced in the upper percentiles in boys. Contrarily, CAP was relatively stable across the age span without considerable difference between boys and girls. We found a significant positive correlation between BMI-SDS and both CAP and LSM for BMI-SDS >1.28. For BMI-SDS < 1.28, the association was also positive but reached statistical significance only for CAP. Further, the association between BMI-SDS and CAP was significantly stronger in younger than in older children. There was no association between pubertal status and CAP. For LSM, we found that children with a high BMI-SDS but not children with normal weight had significantly higher LSM values in Tanner stage 4. Conclusions: Age, sex, pubertal status and weight status should be considered when interpreting LSM and CAP in pediatric patients to facilitate and improve early detection of abnormal liver function, which is associated with common pathologies, such as NAFLD.

Current and projected incidence trends of pediatric-onset inflammatory bowel disease in Germany based on the Saxon Pediatric IBD Registry 2000-2014 -a 15-year evaluation of trends.

AIMS: An increasing number of children and adolescents worldwide suffer from inflammatory bowel disease (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). The present work aims to investigate the incidence, prevalence and future trends of IBD in children and adolescents in Saxony, Germany. METHODS: The Saxon Pediatric IBD Registry collected data on patients up to 15 years of age from all 31 pediatric hospitals and pediatric gastroenterologists in Saxony over a 15-year period (2000-2014). In 2019, an independent survey estimated a registry completeness of 95.7%. Age-standardized incidence rates (ASR) per 100,000 person-years (PY) and prevalence per 100,000 children and adolescents were calculated. Evaluation was also been performed in sex and age subgroups. Joinpoint and Poisson regression were used for trend analyses and projections. RESULTS: 532 patients with confirmed IBD during 2000-2014 were included in the epidemiological evaluation. 63.5% (n = 338) patients had CD, 33.1% (n = 176) had UC and 3.4% (n = 18) had unclassified IBD (IBD-U). The 15-year IBD prevalence was 111.8 [95%-CI: 102.3-121.3] per 100,000. The incidence ASR of IBD per 100,000 PY over the whole observation period was 7.5 [6.9-8.1]. ASR for the subtypes were 4.8 [4.3-5.3] for CD, 2.5 [2.1-2.9] for UC and 0.3 [0.1-0.4] for IBD-U. The trend analysis of ASR using the joinpoint regression confirmed a significant increase for incidence of IBD as well as CD. For IBD, the ASR per 100,000 PY increased from 4.6 [2.8-6.3] in 2000 to 8.2 [7.5-13.6] in 2014; projected incidence rates for IBD in Germany are 12.9 [6.5-25.5] in the year 2025 and 14.9 [6.7-32.8] in 2030, respectively. Thus, the number of new IBD diagnoses in Germany would more than triple (325%) in 2030 compared to 2000. The increase is expected to be faster in CD than UC, and be more in males than in females. The expected number of newly diagnosed children with IBD in Germany is projected to rise to about 1,584 [1,512-1,655] in 2025, and to about 1,918 [1,807-2,29] in 2030. CONCLUSION: The incidence of IBD in children and adolescents in Saxony increased at a similar rate as in other developed countries during the observation period. Given this trend, the health care system must provide adequate resources for the care of these young patients in the future.

Survival Benefits Following Liver Transplantation: A Matched-pair Analysis in Pediatric Patients With Cystic Fibrosis.

OBJECTIVES: Cystic fibrosis-related liver disease (CFLD) with consecutive cirrhosis is the third most common cause of death in CF patients. The aim of this study was to identify the potential long-term benefits of liver transplantation (LTx) in a match-control comparison. METHODS: Retrospective single-center data analysis of all pediatric LTx for CFLD between 1998 and 2014. A control group was selected from the local CF patient registry. Data were collected from case report forms and included clinical and laboratory data, lung function tests, the indication for LTx, and details of surgical procedures. RESULTS: At our institution, 23 patients with severe CFLD median age 13.8 years (range 8.7-17.4; 16 boys) underwent LTx between 1998 and 2014. In all patients, normalization of hepatic CF manifestations were achieved after LTx. But obviously there was no significant positive influence on nutritional status. Signs of posttransplant liver steatosis were documented by ultrasound in 17 patients. Liver biopsies after LTx were performed in 19 patients, in 42% (n = 8) of these biopsies a fatty degeneration was observed. Five patients died after LTx, none because of primary hepatic dysfunction (1 because of posttransplant proliferative disorder, 4 because of infection). Analysis of matched control pairs revealed that liver function, anthropometry, pulmonary function, and life expectancy of CFLD patients with LTx are comparable with matched CF peers without CFLD. CONCLUSIONS: Isolated LTx normalizes the hepatic manifestation of CF disease. LTx enables children and adolescents with severe CFLD to have a comparable prognosis in terms of growth, life expectancy, and lung function as CF patients without advanced liver involvement. Our data clarifies the long-term perspectives of affected patients.

Deciphering the Transcriptomic Heterogeneity of Duodenal Coeliac Disease Biopsies.

Coeliac disease (CD) is a clinically heterogeneous autoimmune disease with variable presentation and progression triggered by gluten intake. Molecular or genetic factors contribute to disease heterogeneity, but the reasons for different outcomes are poorly understood. Transcriptome studies of tissue biopsies from CD patients are scarce. Here, we present a high-resolution analysis of the transcriptomes extracted from duodenal biopsies of 24 children and adolescents with active CD and 21 individuals without CD but with intestinal afflictions as controls. The transcriptomes of CD patients divide into three groups-a mixed group presenting the control cases, and CD-low and CD-high groups referring to lower and higher levels of CD severity. Persistence of symptoms was weakly associated with subgroup, but the highest marsh stages were present in subgroup CD-high, together with the highest cell cycle rates as an indicator of virtually complete villous atrophy. Considerable variation in inflammation-level between subgroups was further deciphered into immune cell types using cell type de-convolution. Self-organizing maps portrayal was applied to provide high-resolution landscapes of the CD-transcriptome. We find asymmetric patterns of miRNA and long non-coding RNA and discuss the effect of epigenetic regulation. Expression of genes involved in interferon gamma signaling represent suitable markers to distinguish CD from non-CD cases. Multiple pathways overlay in CD biopsies in different ways, giving rise to heterogeneous transcriptional patterns, which potentially provide information about etiology and the course of the disease.

Definition and early diagnosis of metabolic syndrome in children.

With this review, we aim to focus the attention on some established as well as new concepts for the metabolic syndrome (MetS) in children and adolescents spanning from definition to recommendations for the diagnostic approach. Even though there is no international commonly used definition of the metabolic syndrome in children and adolescents, all definitions include obesity as precondition for the development of MetS even in children. Obesity is one of the major cardiometabolic risk factors and it is strongly linked to other metabolic diseases like hyperlipidemia, hyperinsulinemia as well as hypertension. The metabolic syndrome is commonly known as a constellation of the mentioned morbidities. Pediatricians and researchers agree that early diagnosis and early interventions of the MetS are important to improve the prevention of cardiovascular disease and type 2 diabetes in adulthood. However, this requires appropriate screening tools for children and adolescents at risk for the MetS and its comorbidities. Due to controversies regarding the definition of MetS and the lack of consensus thresholds for the single components in children and adolescents, there is no internationally accepted diagnostic pathway for MetS available. However, several consensus statements and national guidelines for the assessment of obesity and its comorbidities in children and adolescents are available. Obesity seems to be the driving factor for the development of the other risk factors of MetS. In order to avoid conflicts concerning the definition of overweight and obesity, we recommend using the WHO definition of overweight (one standard deviation body mass index for age and sex and obesity; two standard deviations body mass index for age and sex) in children and adolescents.

Chronic Functional Constipation in Infants and Children.

Functional constipation is a common problem among children. The prevalence worldwide is about 3% and it is accounting for about 3-5% of all visits to pediatricians implicating a significant impact on health care cost. In most children presenting with the symptom constipation no underlying medical disease responsible for the symptom can be found; this is the so-called functional constipation. Functional constipation is characterized by infrequent bowel movements, hard and/or large stools, painful defecation, sometimes in combination with fecal incontinence, and is often accompanied by abdominal pain, without evidence of a structural or biochemical explanation.The recommendation for the management of FC includes a normal intake of fibers and fluids, normal physical activity, and an additional pharmacologic treatment for fecal disimpaction followed by a pharmacologic maintenance therapy.In infants constipation is treated somewhat differently as compared with children. When constipation presents early in life, the risk of an underlying organic disease is increased compared to older children.

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

OBJECTIVES: Assessing the seroprevalence and the prevalence of definite coeliac disease (CD) in the German LIFE Child Health study cohort including immunoglobulin A (IgA) antibodies against tissue transglutaminase (IgA-TTG) in addition to IgG antibodies against deamidated gliadin peptides (IgG-DGP) and human leukocyte antigen (HLA)-DQ2/8 genotyping. METHODS: Samples from children and adolescents were first screened for IgA-TTG and IgG-DGP. If IgA-TTG was above 0.5 times the upper limit of normal and/or IgG-DGP was positive, IgA antibodies against endomysium (IgA-EmA) were measured, and HLA was genotyped. In patients with only IgG-DGP positivity, total IgA was assayed. Subjects with suspicious results were followed up serologically and, in case of repeatedly positive antibody results, invited for a personal interview. Further diagnostic data were obtained independent from our study. RESULTS: We screened 2363 children's blood samples collected from 2011 to 2015. The seroprevalence, that is, IgA-TTG and/or IgA-EmA positivity or IgG-DGP positivity with IgA <0.05 g/L, was 1.57% (95% confidence interval [CI95%] 1.14-2.15). The prevalence of suspected CD, that is, seroprevalence and compatible HLA genotype with hitherto unknown mucosal damage, was 1.35% (CI95% 0.96-1.91). Definite CD, that is, seropositivity accompanied by positive intestinal biopsy or IgA-TTG ≥ 10 × upper limit of normal, was found in 0.42% (CI95% 0.22-0.80). Seven children claimed to have CD. The HLA haplotype, however, matched in only 4 of them resulting in an overall CD prevalence of at least 0.59% (CI95% 0.34-1.02). Thirteen unclear cases remained; therefore, the prevalence may even be higher. CONCLUSIONS: The prevalence of definite CD in a population-representative German cohort is higher than previously described. HLA-DQ typing is helpful to identify false-positive IgA-TTG patients negative for IgA-EmA and/or IgG-DGP under screening conditions and unmasks possible misdiagnoses of CD.

Antibody Concentrations Decrease 14-Fold in Children With Celiac Disease on a Gluten-Free Diet but Remain High at 3 Months.

BACKGROUND & AIMS: Celiac disease can be identified by a serologic test for IgA against tissue transglutaminase (IgA-TTG) in a large proportion of children. However, the increased concentrations of antibody rarely normalize within the months after children are placed on a gluten-free diet (GFD). Early serologic predictors of sufficient adherence to GFD are required for optimal treatment. METHODS: In a prospective study, we observed the response to a GFD in 345 pediatric patients (67% girls; mean age, 8.4 y) who underwent duodenal biopsy to confirm or refute celiac disease from October 2012 through December 2015. Baseline serum samples were tested centrally for IgA-TTG and IgG against deamidated gliadin. Follow-up serologic analyses of children on a GFD were performed about 3 months later. RESULTS: The geometric mean concentration of IgA-TTG decreased from 72.4-fold to 5.2-fold the upper limit of normal (ULN), or by a factor of 14.0 (95% CI, 12.0-16.4). A substantial response (defined as a larger change than the typical variation in patients not on a GFD) was observed in 80.6% of the children. Only 28.1% of patients had a substantial response in the concentration of IgG against deamidated gliadin. Concentration of IgA-TTG remained above 1-fold the ULN in 83.8% of patients, and above 10-fold the ULN in 26.6% of patients with a substantial response. CONCLUSIONS: Serum concentration of IgA-TTG decreases substantially in most children with celiac disease within 3 months after they are placed on a GFD, but does not normalize in most. This information on changes in antibody concentrations can be used to assess patient response to the diet at short-term follow-up evaluations. Patients with a substantial response to a GFD often still have high antibody levels after 3 months. German Clinical Trials Registry no. DRKS00003854.

New pediatric percentiles of liver enzyme serum levels (alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase): Effects of age, sex, body mass index, and pubertal stage.

The present study aims to clarify the effects of sex, age, body mass index (BMI), and puberty on transaminase serum levels in children and adolescents and to provide new age- and sex-related percentiles for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyltransferase (GGT). Venous blood and anthropometric data were collected from 4,126 cases. Excluded were cases of participants with potential hepatotoxic medication, with evidence of potential illness at the time of blood sampling and non-normal BMI (BMI <10th or >90th). The resulting data (N = 3,131 cases) were used for the calculations of ALT, AST, and GGT percentiles. Age- and sex-related reference intervals were established by using an LMS method of Cole-type method. Serum levels of transaminases follow age-specific patterns and relate to the onset of puberty. This observation is more pronounced in girls than in boys. ALT percentiles showed similar-shaped patterns in both sexes. Multivariate regression confirmed significant effects of puberty and BMI-SDS (ß = 2.21) on ALT. Surprisingly, AST serum levels were negatively influenced by age (ß = -1.42) and BMI-SDS (ß = -0.15). GGT percentiles revealed significant sex-specific differences, correlated positively with age (ß = 0.37) and showed significant association with BMI-SDS (ß = 1.16). CONCLUSION: Current reference values of ALT, AST, and GGT serum levels were calculated for children between 11 months and 16.0 years, using modern analytical and statistical methods. This study extends the current knowledge about transaminases by revealing influences of age, sex, BMI, and puberty on serum concentrations of all three parameters and has for these parameters one of the largest sample sizes published so far. (Hepatology 2017).

Novel Insights in the Metabolic Syndrome in Childhood and Adolescence.

Metabolic syndrome (MetS) is recognized as an escalating major health risk in adults as well as in children and adolescents. Its prevalence ranges from 6 to 39% depending on the applied definition criteria. To date, there is no consensus on a MetS definition for children and adolescents. However, most authors agree on essential components such as glucose intolerance, central obesity, hypertension, and dyslipidemia; each representing a risk for cardiovascular disease. Recently, associations between MetS and non-alcoholic fatty liver disease, hyperuricemia, and sleep disturbances have emerged. Biomarkers like adipocytokines are a subject of current research as they are implicated in the pathogenesis of the MetS. Epigenetics and gestational programming, especially the role of microRNA, comprise a novel, rapidly developing and promising research focus on the topic of MetS. MicroRNAs are increasingly valued for potential roles in the diagnosis, stratification, and therapeutics of MetS. Early detection of risk factors, screening for metabolic disturbances, and the identification of new therapies are major aims to reduce morbidity and mortality related to MetS. Dietary modification and physical activity are currently the only adopted treatment approaches. Pharmacological therapies and bariatric surgery are still contradictory and, therefore, are only recommended in selected high-risk cases.

Autoantibodies Against Glycoprotein 2 Isoforms in Pediatric Patients with Inflammatory Bowel Disease.

BACKGROUND: Anti-Glycoprotein 2 (GP2) antibodies are associated with a more complicated course of Crohn's disease (CD) in adults. Four different GP2 isoforms with different length and antibody-binding sites have been identified so far but not been explored in serological studies. We aimed to investigate the diagnostic utility of autoantibodies against all 4 isoforms of GP2 in an exclusively pediatric population for the first time. METHODS: We included 278 children and adolescents with inflammatory bowel disease: 164 with CD, 114 with ulcerative colitis, 83 disease controls (acute gastrointestinal infection, nonspecific gastrointestinal functional disorders), and 219 healthy controls. Sera were tested for anti-GP2 antibodies using 4 different isoforms of GP2 for anti-Saccharomyces cerevisiae antibodies, antineutrophil cytoplasmic antibodies, and pancreatic antibodies. RESULTS: Anti-GP2 antibodies were significantly more prevalent in patients with CD than in ulcerative colitis and controls. We found a sensitivity of 38% (with a specificity of 95%) for anti-GP2 IgG against isoform 4 in CD. Anti-GP2 IgA against isoform 1 and anti-GP2 IgG against isoform 4 possessed the best diagnostic values for identification of CD. For the differentiation of CD from ulcerative colitis anti-GP2 IgG against isoforms 3 and 4 proved to be most accurate markers. Anti-GP2 antibodies were associated with a more complicated disease behavior and bowel surgery in CD. In a subgroup of patients with CD, anti-GP2 IgG against isoform 4 proved to be a relatively stable marker over time independent of disease activity. CONCLUSIONS: Anti-GP2 antibodies against different isoforms are specific markers for CD and for different phenotypes in pediatric inflammatory bowel disease.

Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy.

BACKGROUND & AIMS: A diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures. METHODS: We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease. RESULTS: Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays. CONCLUSIONS: In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854.

Primate liver tissue as an alternative substrate for endomysium antibody immunofluorescence testing in diagnostics of paediatric coeliac disease.

BACKGROUND: Immunofluorescence assays of antibodies against endomysium (EmA) on primate oesophagus sections represent the gold standard in serological testing for coeliac disease (CD). As alternative immunofluorescence technique, staining of primate liver tissue is in use. We compared performance and predictive power of IgA- and IgG-EmA on primate oesophagus and primate liver sections. METHODS: Sera of 298 paediatric biopsy-proven CD patients under gluten-containing diet and 574 disease controls were investigated. Samples were collected between 2004 and 2013 in six children's hospitals. The antibodies were assayed blinded to diagnoses and histological data. Sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were calculated for different assays. RESULTS: (Oesophagus vs liver): For IgA-EmA, sensitivity (0.953 vs 0.956) and specificity (0.981 vs 0.972) as well as PPV (0.963 vs 0.947) and NPV (0.976 vs 0.979) were comparable on both tissues. IgG-EmA on liver showed significantly higher sensitivity (0.520 vs 0.631; p=0.006) but significantly lower specificity (0.995 vs 0.963; p=0.002) and PPV (0.981 vs 0.899; p=0.0002) than on oesophagus. NPV on liver was higher than NPV on oesophagus, however, the difference was not statistically significant (0.799 vs 0.834; p=0.099). CONCLUSION: Primate liver can be used as alternative, equally well functioning substrate for IgA-EmA testing.

Antibodies in the diagnosis of coeliac disease: a biopsy-controlled, international, multicentre study of 376 children with coeliac disease and 695 controls.

Diagnosis of coeliac disease (CD) relies on a combination of clinical, genetic, serological and duodenal morphological findings. The ESPGHAN suggested that biopsy may not be necessary in all cases. New guidelines include omission of biopsy if the concentration of CD-specific antibodies exceeds 10 times the upper limit of normal (10 ULN) and other criteria are met. We analysed the 10 ULN criterion and investigated multiple antibody-assays. Serum was collected from 1071 children with duodenal biopsy (376 CD patients, 695 disease-controls). IgA-antibodies to tissue transglutaminase (IgA-aTTG), IgG-antibodies to deamidated gliadin peptides (IgG-aDGL) and IgA-endomysium antibodies (IgA-EMA) were measured centrally. We considered 3 outcomes for antibody test procedures utilizing IgA-aTTG and/or IgG-aDGL: positive (≥10 ULN, recommend gluten-free diet), negative (<1 ULN, no gluten-free diet) or unclear (perform biopsy). Positive (PPV) and negative (NPV) predictive values were based on clear test results. We required that they and their lower confidence bounds (LCB) be simultaneously very high (LCB >90% and PPV/NPV >95%). These stringent conditions were met for appropriate antibody-procedures over a prevalence range of 9-57%. By combining IgG-aDGL with IgA-aTTG, one could do without assaying total IgA. The PPV of IgG-aDGL was estimated to be extremely high, although more studies are necessary to narrow down the LCB. The proportion of patients requiring a biopsy was <11%. The procedures were either equivalent or even better in children <2 years compared to older children. All 310 of the IgA-aTTG positive children were also IgA-EMA positive. Antibody-assays could render biopsies unnecessary in most children, if experienced paediatric gastroenterologists evaluate the case. This suggestion only applies to the kits used here and should be verified for other available assays. Confirming IgA-aTTG positivity (≥10 ULN) by EMA-testing is unnecessary if performed on the same blood sample. Prospective studies are needed.