A Simple Endoscopic Score Modified for the Upper Gastrointestinal Tract in Crohn's Disease [UGI-SES-CD]: A Report From the ImageKids Study.

OBJECTIVE: There is no standardized endoscopic description of upper gastrointestinal [UGI] disease in Crohn's disease [CD]. We prospectively applied the Simple Endoscopic Score for CD [SES-CD] to the UGI tract as a planned sub-study of the multicentre prospective ImageKids study. We aimed to assess the utility of the UGI-SES-CD and its clinical significance in paediatric CD. DESIGN: Patients underwent an oesophagogastroduodenoscopy [EGD], ileocolonoscopy, and magnetic resonance enterography [MRE] with explicit clinical data recorded. SES-CD was scored at each region [oesophagus, stomach body, antrum, and duodenum]. Half of the patients were followed for 18 months, when a repeat MRE was performed. RESULTS: A total of 202 children were included 56% males, mean age 11.5 ± 3.2 years, median weighted Paediatric Crohn's Disease Activity Index [wPCDAI 25]). UGI-SES-CD score ranged 0-17, with 95 [47%] having a UGI-SES-CD ≥1; no narrowing was detected. UGI-SES-CD ≥1 was associated with higher: wPCDAI [32.5 vs 20; p = 0.03]; Physician's Global Assessment [PGA] of inflammation (45 mm visual analogue score [VAS] vs 30 mm VAS; p = 0.04); ileocolonoscopic SES-CD [10 vs 7; p = 0.004], faecal calprotectin [717 µg/g vs 654 µ/g; p= 0.046]; and radiological global assessment of damage by MRE [7 mm VAS vs 0; p = 0.04]. In all, 81 patients were followed for 18 months and no association was identified between initial UGI SES-CD and markers of disease course such as surgery, MRE assessment, or treatment escalation. CONCLUSION: UGI-SES-CD is an easily reported objective scoring system and is associated with a more severe disease phenotype but not with disease course.

Intestinal anti-transglutaminase 2 immunoglobulin A deposits in children at risk for coeliac disease (CD): data from the PreventCD study.

In coeliac disease (CD), anti-tissue transglutaminase 2 immunoglobulin (Ig)A antibodies (anti-TG2) are produced and deposited in the intestine. PreventCD (www.preventcd.com) is a European multi-centre study, which investigates the influence of infant nutrition and that of genetic, immunological and other environmental factors on the risk of developing CD. The aim of the current study was to evaluate the appearance of intestinal anti-TG2 deposits in very early intestinal biopsies from at-risk infants and their predictive value for villous atrophy. Sixty-five small bowel biopsies, performed in 62 children, were investigated for the presence of intestinal anti-TG2 extracellular IgA deposits by using double immunofluorescence. The biopsies were performed in the presence of elevated serum levels of CD-associated antibodies and/or symptoms suggesting disease. Deposits of anti-TG2 IgA were present in 53 of 53 CD patients and three of three potential CD patients. In potential CD patients, mucosal deposits showed a patchy distribution characterized by some areas completely negative, whereas active CD patients had uniformly present and evident mucosal deposits. Only one of six patients without CD (negative for serum anti-TG2 and with normal mucosa) had intestinal deposits with a patchy distribution and a weak staining. Two of the 53 CD patients received a definitive diagnosis of CD after a second or third biopsy; mucosal deposits of anti-TG2 IgA were evaluated in all samples. Before developing villous atrophy, both patients had anti-TG2 deposits in normal mucosal architecture, antibodies in one patient being absent in serum. We demonstrated that in CD the intestinal deposits of anti-TG2 are a constant presence and appear very early in the natural history of disease.

[Is it time for mass screening for celiac disease?]. / Is het tijd voor bevolkingsonderzoek naar coeliakie?

Celiac disease is a common condition with a variable presentation, and is frequently not recognized by the physician. Although a gluten-free diet has a positive effect on the health of the celiac patient, prevention would be even more beneficial. In this article we outline the different possibilities for primary and secondary prevention of celiac disease. Results of recent prospective studies show that at this moment primary prevention is not possible, but secondary preventive strategies can be applied to decrease the morbidity associated with this disease; mass screening is one option. Results of recent studies concerning this topic will be discussed.

Systematic review with meta-analysis: early infant feeding and coeliac disease--update 2015.

BACKGROUND: New evidence emerged on early feeding practices and the risk of coeliac disease. AIM: To systematically update evidence on these practices to find out whether there is a need to revise current recommendations. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from July 2012 (end of last search) to February 2015 for studies of any design that assessed the effect of gluten consumption and breastfeeding on the development of coeliac disease and/or coeliac disease-related autoimmunity. RESULTS: We identified 21 publications, including two, new, large, randomised controlled trials performed in high-risk infants. Exclusive or any breastfeeding, as well as breastfeeding at the time of gluten introduction, did not reduce the risk of developing coeliac disease during childhood. For infants at high risk of developing coeliac disease, gluten introduction at 4 months of age in very small amounts, or at 6 or 12 months of age, resulted in similar rates of coeliac disease diagnosis in early childhood. Later gluten introduction was associated with later development of coeliac specific autoimmunity and coeliac disease during childhood, but not total risk reduction. Observational studies indicate that consumption of a higher amount of gluten at weaning may increase the risk for coeliac disease development. CONCLUSIONS: Infant feeding practices (breastfeeding, time of gluten introduction) have no effect on the risk of developing coeliac disease during childhood (at least at specific timeframes evaluated in the included studies), necessitating an update of current European recommendations.

Management guidelines of eosinophilic esophagitis in childhood.

OBJECTIVES: Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor-responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. METHODS: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. RESULTS: The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid-based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. CONCLUSIONS: EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

A practical guide for the diagnosis of primary enteric nervous system disorders.

OBJECTIVE: Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field. RESULTS: Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance. CONCLUSIONS: The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

[Gluten tolerance as a result of earlier exposure?]. / Tolerantie voor gluten door vroegere blootstelling?

In a recently published article in Pediatrics on the Swedish coeliac disease 'epidemic', it is suggested that the gradual introduction of gluten-containing foods from 4 months of age, preferably while breastfeeding is still ongoing, is favourable for the prevention of coeliac disease. This stirred up the discussion about the timing of introduction of gluten to the diet of infants in the Netherlands, where gluten-containing foods are mostly introduced from 6 months of age onwards. The retrospective character of data collection, however, has to be taken into account when interpreting the Swedish study. Future results of prospective studies on gluten introduction and coeliac disease, such as the PreventCD family study (www.preventcd.com), should provide the information necessary for deciding on a change in the Dutch guidelines for the introduction of gluten to the diet of young children.

Systematic review: early infant feeding and the prevention of coeliac disease.

BACKGROUND: PREVENTCD, Prevent Coeliac Disease, is an international project investigating the hypothesis of possible induction of tolerance to gluten in genetically predisposed children through introducing small quantities of gluten during the period of breastfeeding. AIM: To summarise current knowledge on the possible relationship between early feeding practices and the risk of coeliac disease (CD). METHODS: The Cochrane Library, MEDLINE, and EMBASE databases were searched in May 2011, and the search was updated in January 2012, and again in July 2012. RESULTS: Breastfeeding (BF) and CD: some studies show a protective effect of BF, while others show no effect. No studies have shown a long-term preventive effect. BF at the time of gluten introduction and CD: Results from a meta-analysis of five observational case-control studies suggest that BF at gluten introduction is associated with a lower risk of CD compared with formula feeding. It is unclear whether BF provides a permanent protection or only delays the onset of CD. Timing of gluten introduction: The data suggest that both early (≤4 months) and late (≥7 months) introduction of gluten may increase the risk of CD. Amount of gluten at weaning (and later) and CD: One incident case-referent study documented that the introduction of gluten in large amounts compared with small or medium amounts increased the risk of CD. CONCLUSIONS: In the absence of clear evidence, in order to decrease the risk of later coeliac disease, it is reasonable to avoid both early (<4 months) and late (≥7 months) introduction of gluten, and to introduce gluten while the infant is still being breastfed. Future studies may clarify the remaining uncertainties.

Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines.

OBJECTIVES: This guideline provides recommendations for the diagnosis and management of suspected cow's-milk protein allergy (CMPA) in Europe. It presents a practical approach with a diagnostic algorithm and is based on recently published evidence-based guidelines on CMPA. DIAGNOSIS: If CMPA is suspected by history and examination, then strict allergen avoidance is initiated. In certain circumstances (eg, a clear history of immediate symptoms, a life-threatening reaction with a positive test for CMP-specific IgE), the diagnosis can be made without a milk challenge. In all other circumstances, a controlled oral food challenge (open or blind) under medical supervision is required to confirm or exclude the diagnosis of CMPA. TREATMENT: In breast-fed infants, the mother should start a strict CMP-free diet. Non-breast-fed infants with confirmed CMPA should receive an extensively hydrolyzed protein-based formula with proven efficacy in appropriate clinical trials; amino acids-based formulae are reserved for certain situations. Soy protein formula, if tolerated, is an option beyond 6 months of age. Nutritional counseling and regular monitoring of growth are mandatory in all age groups requiring CMP exclusion. REEVALUATION: Patients should be reevaluated every 6 to 12 months to assess whether they have developed tolerance to CMP. This is achieved in >75% by 3 years of age and >90% by 6 years of age. Inappropriate or overly long dietary eliminations should be avoided. Such restrictions may impair the quality of life of both child and family, induce improper growth, and incur unnecessary health care costs.

Coeliac disease diagnosis: ESPGHAN 1990 criteria or need for a change? Results of a questionnaire.

BACKGROUND AND OBJECTIVES: A revision of criteria for diagnosing coeliac disease (CD) is being conducted by The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In parallel, we have performed a survey aimed to evaluate present practices for CD among paediatric gastroenterologists and to learn their views on the need for modification of present criteria for CD diagnosis. PATIENTS AND METHODS: Questionnaires were distributed to experienced paediatric gastroenterologists (ESPGHAN members) via the Internet. RESULTS: Overall, 95 valid questionnaires were available for analysis, pertaining to 28 different countries, with the majority of responders treating patients with CD for >15 years. Only about 12% of the responders comply with present criteria, noncompliance being related mainly to the challenge policy. Approximately 90% request a revision and modification of the present criteria. Forty-four percent want to omit the small bowel biopsy in symptomatic children with positive anti-tissue transglutaminase immunoglobulin (Ig) A or endomysial IgA antibodies, especially if they are DQ2/DQ8 positive. For silent cases detected by screening with convincingly positive anti-tissue transglutaminase IgA or EMA IgA, about 30% consider that no small bowel biopsy should be required in selected cases. Adding human leukocyte antigen typing in the diagnostic workup was asked for by 42% of the responders. As for gluten challenge, a new policy is advocated restricting its obligation to cases whenever the diagnosis is doubtful or unclear. CONCLUSIONS: Based on these opinions, revision of the ESPGHAN criteria for diagnosing CD is urgently needed.

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease.

OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

Childhood coeliac disease: towards an improved serological mass screening strategy.

BACKGROUND: In 1997-1998, 6127 asymptomatic children aged 2-4 years were screened for coeliac disease (CD) by anti-endomysium (EmA) testing in the Netherlands. After 6 (+/-2) months, biopsies were performed in 57 seropositive children; 31(54%) had villous atrophy, but 26 (46%), all HLA-DQ2/DQ8 positive, had normal histology. AIMS: To reduce the number of unnecessary biopsies after serological mass screening for CD in asymptomatic young children by optimizing screening procedures. METHODS: Comparing different tests and optimizing their cut-off point: screening samples were tested for EmA, tissue-transglutaminase (tTGA), antigliadin and deamidated-gliadin-peptides (anti-DGP) antibodies. Determining serological persistence over time: persistence of EmA and tTGA was determined by testing serological samples obtained at biopsy. RESULTS: Tissue-transglutaminase and anti-DGP correlated with EmA. Optimization of standard cut-off points not only reduced unnecessary biopsies by 50-96% but also reduced sensitivity. EmA persisted in all CD children, but in only 50% of the non-CD children. tTGA persisted in 83% of CD, but in only 15% of non-CD children. CONCLUSIONS: Coeliac disease antibodies may be present transiently in genetically predisposed children. To avoid unnecessary biopsies, serological mass screening procedures may be improved by repeating EmA and/or tTGA in initially seropositive young children after 6 months, before proceeding to biopsy. This may reduce the number of unnecessary biopsies that are performed.

A girl with type 1 diabetes and a yellowish appearance.

Type 1 diabetes mellitus in children has been associated with other autoimmune diseases, especially coeliac disease and autoimmune thyroiditis. This association may be the result of a common pathogenic background. We describe the case of a girl with type 1 diabetes mellitus who developed icterus due to autoimmune hepatitis, a disease rarely found in children. Thyroiditis-associated and diabetes-associated autoantibodies were also present. Human leucocyte antigen typing revealed DRB1*03 heterozygosity, which has been associated with the occurrence of both autoimmune hepatitis and type 1 diabetes. This finding implies that similar pathogenic pathways may be involved in different autoimmune diseases including type 1 diabetes and autoimmune hepatitis. The patient was successfully treated with prednisolone and azathioprine. Autoimmune hepatitis can be a serious co-occurring disease in patients with type 1 diabetes.

Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.

OBJECTIVE: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. DESIGN: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). RESULTS: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. CONCLUSIONS: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

Review article: future research on coeliac disease - a position report from the European multistakeholder platform on coeliac disease (CDEUSSA).

BACKGROUND: CDEUSSA is a Specific Support Action project from the Sixth Framework Programme Priority of the European Union (EU). Its aim is to bring together basic and applied research in the area of coeliac disease (CD). This paper reviews the main issues that are a result of the CDEUSSA initiative. AIM: To identify the major issues in need of investigation in the areas of clinical aspects, treatment, prevention and public health. METHODS: Key stakeholders, representing a wide range of knowledge with crucial importance for CD research and practice, have participated in two workshops aimed at identifying and proposing to the EU, as high priority research, topics in the areas of clinical aspects, treatment, prevention and public health. RESULTS: In public health, the overall goal should be to improve quality of life of the European population by implementing primary prevention strategies, early diagnosis and improved treatments for CD. New treatment strategies need to be developed. The option of primary prevention should be fully explored, which requires combined epidemiological, clinical and basic scientific research efforts. Such studies should also consider the importance of gene-environment interactions in the development of CD. Increased knowledge is needed on the natural history of CD. Diagnostic criteria need to be revised. CONCLUSIONS: To achieve these goals, a collaboration of the stakeholders is fundamental, including research and patient organizations, as well as industries within both diagnostics and food production.

Coeliac disease in The Netherlands.

BACKGROUND: The prevalence of adult coeliac disease in The Netherlands was studied in the Dutch Coeliac Disease Society and in blood donors but not in the general population. We therefore studied the prevalence of recognized and unrecognized coeliac disease in a large cohort, representative of the adult Dutch general population. Blood samples were available for anonymous research, as well as data on dietary habits, self-reported physical characteristics, health problems, quality of life and socio-economic circumstances. METHODS: Subjects included 50,760 individuals who had previously participated in two large population-based studies on health status in relation to lifestyle factors. Recognized coeliac disease was studied in all subjects by identification of self-reported adherence to a gluten-free diet and subsequent confirmation of the diagnosis of coeliac disease. Unrecognized coeliac disease was studied in a random sample of 1440 out of the 50,760 subjects through serologic screening and human lymphocyte antigen (HLA) typing. RESULTS: The prevalence of recognized coeliac disease was 0.016% (95% confidence interval 0.008-0.031) and of unrecognized coeliac disease 0.35% (95% confidence interval 0.15-0.81). Menarcheal age was higher in women with recognized coeliac disease than in women without coeliac disease. CONCLUSIONS: The prevalence of adult recognized coeliac disease in The Netherlands is one of the lowest in Europe, while the prevalence of unrecognized coeliac disease is comparable with that in other European countries. Adult coeliac disease is strongly under diagnosed in The Netherlands. The higher menarcheal age in women with recognized coeliac disease may be explained by diagnostic delay.

Tube feeding and bone marrow transplantation.

BACKGROUND: Children undergoing bone marrow transplantation (BMT) have poor oral intake during the transplant period, caused mainly by the intensive therapy used for their conditioning. Nutritional support (NS) is almost always needed. Whenever possible, tube feeding (TF) is preferred to parenteral nutrition (PN) because its more physiologic and causes fewer complications. However, children undergoing BMT are usually parenterally fed. We, therefore, studied whether TF was tolerated in children undergoing BMT and whether the nutritional intake was adequate in comparison to PN. PROCEDURE: Two groups were compared: TF (n = 12) and PN (n = 22). If intolerance for TF occurred, additional or total PN was given. Nutritional status, intake, complications, and costs were assessed. RESULTS: Both groups had an adequate nutritional status and reached 85% of their nutritional requirements. TF was possible in 62% of the NS days and three children could be exclusively fed with TF. A longer pre-transplant duration of TF seemed to increase the enteral tolerance. Gastrointestinal symptoms were equally frequent in TF as in PN, but cholestasis was less frequent in TF. The mean nutritional cost per child in the TF group was 440 US dollars less than in the PN group. CONCLUSIONS: TF is possible and equal in efficacy to PN in children undergoing BMT, and may have budgetary benefits.

Adult height in patients with early onset of Crohn's disease.

BACKGROUND: Growth impairment during childhood and adolescence is a common problem faced by patients with an early onset of Crohn's disease. AIMS: To establish how the final adult height is affected in patients with early onset of symptoms of Crohn's disease. METHODS: Information on height, parental height, and disease history was obtained from 135 patients with Crohn's disease who reached their adult height (men 22-40 years, women 18-40 years) using a questionnaire and by outpatient measurement of height where possible. Subsequently, adult heights were expressed as standard deviation scores, with and without correction for the expected target height. RESULTS: Patients with onset of disease before puberty were shorter compared with patients with onset in adulthood (p<0.01). This difference was not statistically significant when adult heights were corrected for parental height. Also, height standard deviation scores for those patients with onset of disease before puberty were significantly lower than those with onset of disease during puberty (p<0.05) but after correction for parental height the difference was not significant. The site of disease had no influence on adult height. Patients who had used corticosteroids during puberty were significantly shorter than patients who had not (p=0.005). This was also true when corrected for target height (p=0.007). CONCLUSIONS: Although there was a trend indicating a deficit in adult height in patients with an early onset of Crohn's disease, once adjustment was made for parental height, this difference was not significant. Use of corticosteroids in puberty resulted in lower adult height.