Prediction Models for Celiac Disease Development in Children From High-Risk Families: Data From the PreventCD Cohort.

BACKGROUND & AIMS: Screening for celiac disease (CD) is recommended in children with affected first-degree relatives (FDR). However, the frequency of screening and at what age remain unknown. The aims of this study were to detect variables influencing the risk of CD development and develop and validate clinical prediction models to provide individualized screening advice. METHODS: We analyzed prospective data from the 10 years of follow-up of the PreventCD-birth cohort involving 944 genetically predisposed children with CD-FDR. Variables significantly influencing the CD risk were combined to determine a risk score. Landmark analyses were performed at different ages. Prediction models were created using multivariable Cox proportional hazards regression analyses, backward elimination, and Harrell's c-index for discrimination. Validation was done using data from the independent NeoCel cohort. RESULTS: In March 2019, the median follow-up was 8.3 years (22 days-12.0 years); 135/944 children developed CD (mean age, 4.3 years [range, 1.1-11.4]). CD developed significantly more often in girls (P = .005) and in Human Leukocyte Antigen (HLA)-DQ2 homozygous individuals (8-year cumulative incidence rate of 35.4% vs maximum of the other HLA-risk groups 18.2% [P < .001]). The effect of homozygosity DR3-DQ2/DR7-DQ2 on CD development was only present in girls (interaction P = .04). The prediction models showed good fit in the validation cohort (Cox regression 0.81 [0.54]). To calculate a personalized risk of CD development and provide screening advice, we designed the Prediction application https://hputter.shinyapps.io/preventcd/. CONCLUSION: Children with CD-FDR develop CD early in life, and their risk depends on gender, age and HLA-DQ, which are all factors that are important for sound screening advice. These children should be screened early in life, including HLA-DQ2/8-typing, and if genetically predisposed to CD, they should get further personalized screening advice using our Prediction application. TRIAL REGISTRATION NUMBER: ISRCTN74582487 (https://www.isrctn.com/search?q=ISRCTN74582487).

Circulating miRNAs as Potential Biomarkers for Celiac Disease Development.

Background & Aims: Celiac disease (CeD), an immune-mediated disease with enteropathy triggered by gluten, affects ~1% of the general European population. Currently, there are no biomarkers to predict CeD development. MicroRNAs (miRNAs) are short RNAs involved in post-transcriptional gene regulation, and certain disease- and stage-specific miRNA profiles have been found previously. We aimed to investigate whether circulating miRNAs can predict the development of CeD. Methods: Using next-generation miRNA-sequencing, we determined miRNAs in >200 serum samples from 53 participants of the PreventCD study, of whom 33 developed CeD during follow-up. Following study inclusion at 3 months of age, samples were drawn at predefined ages, diagnosis (first anti-transglutaminase antibody (TGA) positivity or diagnostic biopsy) and after the start of a gluten-free diet (GFD). This allowed identification of circulating miRNAs that are deregulated before TGA positivity. For validation of the biomarkers for CeD and GFD response, two additional cohorts were included in subsequent meta-analyses. Additionally, miRNAs were measured in duodenal biopsies in a case-control cohort. Results: 53 circulating miRNAs were increased (27) or decreased (26) in CeD versus controls. We assessed specific trends in these individual miRNAs in the PreventCD cohort by grouping the pre-diagnostic samples of the CeD patients (all had negative TGA) by how close to seroconversion (first sample positive TGA) the samples were taken. 8/53 miRNAs differed significantly between controls and samples taken <1 year before TGA positivity: miR-21-3p, miR-374a-5p, 144-3p, miR-500a-3p, miR-486-3p let-7d-3p, let-7e-5p and miR-3605-3p. 6/26 downregulated miRNAs reconstituted upon GFD, including miR-150-5p/-3p, whereas no upregulated miRNAs were downregulated upon GFD. 15/53 biomarker candidates also differed between CeD biopsies and controls, with a concordant direction, indicating that these circulating miRNAs might originate from the intestine. Conclusions: We identified 53 circulating miRNAs that are potential early biomarkers for CeD, of which several can be detected more than a year before TGA positivity and some start to normalize upon GFD.

Efficient implementation of the 'non-biopsy approach' for the diagnosis of childhood celiac disease in the Netherlands: a national prospective evaluation 2010-2013.

The aim of this study was (1) to prospectively evaluate the nationwide implementation of the ESPGHAN-guidelines for the diagnosis of celiac disease (CD), (2) to investigate the incidence and clinical presentation of diagnosed childhood CD (0-14 years) in the Netherlands, and (3) to compare the findings with national survey data from 1975 to 1990 and 1993 to 2000 using the same approach. From 2010 to 2013, all practicing paediatricians were invited to report new celiac diagnoses to the Dutch Pediatric Surveillance Unit. Data were collected via questionnaires. A total of 1107 children with newly diagnosed CD were reported (mean age, 5.8 years; range, 10 months-14.9 years; 60.5% female). After the introduction of the non-biopsy approach in 2012, 75% of the diagnoses were made according to the guideline with a significant decrease of 46.3% in biopsies. The use of EMA and HLA-typing significantly increased with 25.8% and 62.1%, respectively. The overall incidence rate of childhood CD was 8.8-fold higher than in 1975-1990 and 2.0-fold higher than in 1993-2000. During the study period, the prevalence of diagnosed CD was 0.14%, far below 0.7% of CD identified via screening in the general Dutch paediatric population. Clinical presentation has shifted towards less severe and extra-intestinal symptoms.Conclusion: ESPGHAN guidelines for CD diagnosis in children were effectively and rapidly implemented in the Netherlands. Incidence of diagnosed CD among children is still significantly rising with a continuous changing clinical presentation. Despite the increasing incidence of diagnoses, significant underdiagnosis still remains. What is Known: • Since 2000 the incidence of diagnosed childhood CD in the Netherlands has shown a steady rise. • The rise in incidence has been accompanied by a changing clinical presentation at diagnosis. What is New: • The ESPGHAN guidelines 2012 for CD diagnosis were effectively and rapidly implemented in the Netherlands. • The incidence of diagnosed childhood CD in the Netherlands has continued to rise significantly during the reported period.

Breast-Milk Microbiota Linked to Celiac Disease Development in Children: A Pilot Study From the PreventCD Cohort.

Celiac disease (CeD) is an immune-mediated disorder triggered by exposure to dietary gluten proteins in genetically predisposed individuals. In addition to the host genome, the microbiome has recently been linked to CeD risk and pathogenesis. To progress in our understanding of the role of breast milk microbiota profiles in CeD, we have analyzed samples from a sub-set of mothers (n = 49) included in the PreventCD project, whose children did or did not develop CeD. The results of the microbiota data analysis indicated that neither the BMI, HLA-DQ genotype, the CeD condition nor the gluten-free diet of the mothers could explain the human milk microbiota profiles. Nevertheless, we found that origin country, the offspring's birth date and, consequently, the milk sampling date influenced the abundance and prevalence of microbes in human milk, undergoing a transition from an anaerobic to a more aerobic microbiota, including potential pathogenic species. Furthermore, certain microbial species were more abundant in milk samples from mothers whose children went on to develop CeD compared to those that remained healthy. These included increases in facultative methylotrophs such as Methylobacterium komagatae and Methylocapsa palsarum as well as in species such as Bacteroides vulgatus, that consumes fucosylated-oligosaccharides present in human milk, and other breast-abscess associated species. Theoretically, these microbiota components could be vertically transmitted from mothers-to-infants during breastfeeding, thereby influencing CeD risk.

Does infant feeding modulate the manifestation of celiac disease and type 1 diabetes?

PURPOSE OF REVIEW: The review aims to critically discuss the role of infant feeding in the development of celiac disease and type 1 diabetes (T1D). RECENT FINDINGS: Prospective observational and randomized interventional studies show that breastfeeding (BF) or BF during gluten introduction does not reduce the risk of developing CD, but high gluten consumption before age 2 years increased the risk in Swedish children.Despite evidence from retrospective studies, prospective trials failed to find a protective effect of breastfeeding against the risk of T1D development. Nevertheless, breastfeeding at the time of cereal introduction decreases this risk. There is some evidence demonstrating that early exposure to sugar-sweetened beverages increases the risk of T1D in childhood, whereas the timing of gluten introduction, except if introduced very early, does not affect it. SUMMARY: Breastfeeding and/or timing of gluten introduction does not influence celiac disease risk. Breastfeeding at the time of cereal introduction might be protective against T1D. The introduction of certain solid foods at an early age may be associated with the risk of T1D.

Coeliac disease and noncoeliac gluten sensitivity.

The spectrum of gluten-related disorders was restricted to coeliac disease and wheat allergy, but the new contemporary entity referred to as noncoeliac gluten sensitivity has gained recognition mainly in adults but also in children. Noncoeliac gluten sensitivity is defined as the presence of a variety of symptoms related to gluten ingestion in patients in whom coeliac disease and wheat allergy have been excluded. The pathophysiology and biomarkers of coeliac disease and wheat allergy are well known, but this is not the case for noncoeliac gluten sensitivity. It is also not clear whether noncoeliac gluten sensitivity is caused by consumption of gluten or by consumption of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. Randomized trials on noncoeliac gluten sensitivity in children are lacking and are hardly needed to evaluate its role in paediatric patients with gastroenterology to avoid the use of unnecessary restrictive diets in children and interference with proper diagnosis of coeliac disease.

[Hyperglycaemic crises in children and adolescents]. / Hyperglykemische ontregeling bij kinderen en adolescenten.

Recently the Paediatric Association of the Netherlands (NVK) published a new guideline on the treatment of diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar syndrome (HHS) in children and adolescents. DKA comprises hyperglycaemia, ketosis and acidosis. Cerebral oedema is a feared, life-threatening complication of DKA. HHS is characterized by hyperglycaemia, hyperosmolarity, severe dehydration, and little or no ketone production. Multi-organ failure, rhabdomyolysis and thrombosis are the most common complications. The NVK guideline distinguishes between treatment of DKA and treatment of HHS, in contrast with the draft version of the Netherlands Association of Internal Medicine guideline on diabetes. To prevent cerebral oedema in children with DKA, it is necessary that both rehydration and metabolic correction are done slowly and carefully. Use of hypotonic fluids is not recommended. Correction of hyperglycaemia is of secondary importance and insulin should be started at a low dosage. Correction of intravascular hypovolaemia is the most important treatment in children with HHS. If adequate fluid replacement does not cause serum glucose levels to drop sufficiently, then administration of insulin should be considered. Fluid replacement is the initial treatment of HHS. Insulin administration should be considered when serum glucose concentrations are no longer declining adequately with fluid administration alone.