Systematic review: early feeding practices and the risk of coeliac disease. A 2022 update and revision.

BACKGROUND: The effects of early feeding practices on the risk of coeliac disease (CD) remain debated. AIMS: To update evidence on these practices on the risk of CD and/or CD-related autoimmunity (CDA), defined as anti-transglutaminase or anti-endomysial antibody positivity METHODS: We searched MEDLINE, EMBASE and the Cochrane Library to May 2022 for randomised controlled trials (RCTs) and observational studies. RESULTS: We included 36 publications (30 studies). In the population at genetic risk of developing CD (HLA DQ2/DQ8-positive), exclusive or any breastfeeding and longer breastfeeding duration did not reduce the risk of developing CD/CDA during childhood. While a meta-analysis of four case-control studies showed a decreased risk for CD when gluten was introduced during breastfeeding, this was not shown in RCTs and cohort studies. Age at gluten introduction was not associated with cumulative CD/CDA risk, although two RCTs suggested that earlier gluten introduction was associated with earlier CDA appearance. Evidence from six observational studies suggests that consumption of a higher amount of gluten at weaning and/or thereafter may increase CD risk. There is insufficient evidence to determine the amount of gluten associated with an increased CD/CDA risk. Regarding whether infant feeding practices modulate the risk conferred by different HLA genotypes results were inconsistent. CONCLUSIONS: For the population at genetic risk of CD, breastfeeding and age at gluten introduction have no effect on its cumulative incidence during childhood. There is some evidence for an effect of the amount of gluten consumed at weaning and/or thereafter on CD/CDA risk.

ESPGHAN Position Paper on Management and Follow-up of Children and Adolescents With Celiac Disease.

OBJECTIVES: To gather the current evidence and to offer recommendations for follow-up and management. METHODS: The Special Interest Group on Celiac Diseases of the European Society of Paediatric Gastroenterology Hepatology and Nutrition formulated ten questions considered to be essential for follow-up care. A literature search (January 2010-March 2020) was performed in PubMed or Medline. Relevant publications were identified and potentially eligible studies were assessed. Statements and recommendations were developed and discussed by all coauthors. Recommendations were voted upon: joint agreement was set as at least 85%. RESULTS: Publications (n = 2775) were identified and 164 were included. Using evidence or expert opinion, 37 recommendations were formulated on: The need to perform follow-up, its frequency and what should be assessed, how to assess adherence to the gluten-free diet, when to expect catch-up growth, how to treat anemia, how to approach persistent high serum levels of antibodies against tissue-transglutaminase, the indication to perform biopsies, assessment of quality of life, management of children with unclear diagnosis for which a gluten-challenge is indicated, children with associated type 1 diabetes or IgA deficiency, cases of potential celiac disease, which professionals should perform follow-up, how to improve the communication to patients and their parents/caregivers and transition from pediatric to adult health care. CONCLUSIONS: We offer recommendations to improve follow-up of children and adolescents with celiac disease and highlight gaps that should be investigated to further improve management.

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).

Early Feeding Practices and Celiac Disease Prevention: Protocol for an Updated and Revised Systematic Review and Meta-Analysis.

Uncertainty remains in regard to when, how, and in what form gluten should be introduced into the diet, particularly of infants genetically predisposed to developing celiac disease (CD). MEDLINE (PubMed), EMBASE, and Cochrane Central Register of Controlled Trials databases will be searched from inception. Randomized controlled trials (RCTs) and observational studies (cohort, case-control, or cross-sectional studies) investigating the association between early feeding practices and the risk of CD and/or CD autoimmunity will be included. In prospective studies, participants will be infants regardless of the risk of developing CD. For retrospective studies, participants will be children or adults with CD or presenting with positive serology indicative of CD. Interventions will be gluten-containing products of any type. Exposures will be breastfeeding and/or the introduction of gluten-containing products of any type. In control groups, there will be no exposure, different degrees of exposure (partial vs. exclusive breastfeeding, different amounts of gluten, etc.), or a placebo. The primary outcome measure will be CD or CD autoimmunity (i.e., anti-transglutaminase or anti-endomysial antibodies). At least two reviewers will independently assess the risk of bias using a validated risk assessment tool depending on study design. Disagreements will be resolved by discussion to achieve a consensus with the involvement of one or more additional reviewers if required. If appropriate, data will be pooled. If not, a narrative synthesis will be performed. The findings will be submitted to a peer-reviewed journal.

Review on pediatric coeliac disease from a clinical perspective.

Coeliac disease is an immune-mediated condition characterized by chronic inflammation of the small bowel with villous atrophy driven by gluten ingestion in genetically predisposed individuals. It occurs frequently in both children and adults, affecting 1-4% of the population. The disease is associated with both gastrointestinal and extra-intestinal symptoms related to malabsorption and/or immune activation, and autoantibodies to tissue transglutaminase. Removal of gluten from the diet results in resolution of symptoms and enteropathy in the majority of patients. A good diagnostic work-up is important to avoid unnecessary restrictive diets in children. In this review on pediatric coeliac disease, we address epidemiology including predisposing environmental factors and possible preventive strategies, as well as the clinical presentation, diagnosis and follow-up. What is Known: •Primary prevention of coeliac disease is not possible; however, secondary prevention by targeting high-risk groups is recommended. •The diagnosis is safe without duodenal biopsies if specific conditions are met, also in asymptomatic children. What is New: •HLA-DQ typing is not routinely required for the diagnosis, whereas it can rule out coeliac disease if HLA-DQ2 and HLA-DQ8 are absent. •Follow-up could be improved by a more rational use of (laboratory) tests, increased intention to dietary compliance and quality of life.

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.

Growth rate of coeliac children is compromised before the onset of the disease.

INTRODUCTION: Growth impairment has often been described in children who develop coeliac disease (CD). Based on data from the multicentre, longitudinal PreventCD study, we analysed the growth patterns of infants at genetic risk of CD, comparing those who developed CD by 6 years of age (CD 'cases', 113 infants) versus those who did not develop CD by 6 years (no CD 'controls', 831 infants). METHODS: Weight and length/height were measured using a longitudinal protocol. Raw measurements were standardised, computing z-scores for length/height and weight; a linear mixed model was fitted to the data in order to compare the rate of growth in the two cohorts. RESULTS: Neither cases nor controls had significant growth failure. However, when the mean z-scores for weight and height were analysed, there was a difference between the two groups starting at fourth month of life. When the growth pattern in the first year was analysed longitudinally using mixed models, it emerged that children who develop CD had a significantly lower growth rate in weight z-score (-0.028/month; 95% CI -0.038 to -0.017; p<0.001) and in length/height z-score (-0.018/month; 95% CI -0.031 to -0.005; p=0.008) than those who do not develop CD. When the whole follow-up period was analysed (0-6 years), differences between groups in both weight and length/height z-scores were confirmed. CONCLUSION: The growth of children at risk of CD rarely fell below 'clinical standards'. However, growth rate was significantly lower in cases than in controls. Our data suggest that peculiar pathways of growth are present in children who develop CD, long before any clinical or serological signs of the disease appear.

Celiac Disease Prevention.

Celiac disease (CD) is a common autoimmune disorder induced by ingestion of gluten in genetically susceptible individuals. Despite the prerequisite for a genetic predisposition, only a minority of the 40% of the Caucasian population that has this genetic predisposition develops the disease. Thus, environmental and/or lifestyle factors play a causal role in the development of CD. The incidence of CD has increased over the last half-century, resulting in rising interest in identifying risk factors for CD to enable primary prevention. Early infant feeding practices have been suggested as one of the factors influencing the risk of CD in genetically susceptible individuals. However, recent large prospective studies have shown that neither the timing of gluten introduction nor the duration or maintenance of breastfeeding influence the risk of CD. Also, other environmental influences have been investigated as potential risk factors, but have not led to primary prevention strategies. Secondary prevention is possible through early diagnosis and treatment. Since CD is significantly underdiagnosed and a large proportion of CD patients are asymptomatic at the time of diagnosis, secondary prevention will not identify all CD patients, as long as mass screening has not been introduced. As following a gluten-free diet is a major challenge, tertiary prevention strategies are discussed as well.

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.