Celiac Disease Affects 1% of Global Population: Who Will Manage All These Patients?

Celiac disease is a common gastrointestinal condition with an estimated global prevalence of up to 1%. Adequate long-term surveillance of patients is imperative to ensure strict adherence to treatment with a gluten-free diet and the ensuing clinical and histologic recovery. Traditionally, this has been accomplished by means of regular on-site attendance at specialist health care facilities, accompanied for most patients by follow-up endoscopic and laboratory tests. However, the rapidly increasing prevalence of celiac disease and the limited health care resources challenge the current centralized and nonindividualized follow-up strategies. The improved noninvasive surveillance tools and online health care services are further changing the landscape of celiac disease management. There is a clear need for more personalized and on-demand follow-up based on early treatment response and patient-related factors associated with long-term prognosis. Additional scientific evidence on the optimal implementation of follow-up for pediatric and adulthood celiac disease is nevertheless called for.

Measured levels of positive transglutaminase 2 antibodies are not associated with presentation or incidental endoscopic findings at celiac disease diagnosis.

OBJECTIVES: It has been suggested that celiac disease could be diagnosed non-invasively in adults with transglutaminase antibody (TGA) levels >10x upper limit of normal (ULN). It is, however, unclear if high values signify more advanced disease and higher risk of co-morbidities. We investigated the association between the TGA levels, clinical characteristics and non-celiac endoscopic findings. METHODS: Medical data on 450 celiac disease patients at diagnosis were collected. They were further divided into those with high positive (>10x ULN, n = 164), moderately positive (1-10x ULN, n = 219), and negative (n = 67) TGA. RESULTS: Median age of patients was 50 years and 60% were women. Patients with negative TGA were older (median age 58 vs. 51 vs. 46 years respectively, p = 0.002) and had more often weight loss (27% vs. 10% vs. 9%, p < 0.001) and abdominal pain or dyspepsia (40% vs 27% vs. 22%, p = 0.017) than did those with moderately positive/high TGA. The groups did not differ in sex, BMI, or other symptoms. Major endoscopic findings included one esophageal adenocarcinoma presenting with dysphagia, six esophagitis, three gastric ulcers, and 39 H. Pylori or other active gastritis. High, moderately positive or negative TGA levels were not associated with these findings in crude or age-adjusted analyses. CONCLUSIONS: Presentation was similar in patients with moderate or high levels of TGA, whereas patients with negative TGA were different. The level of TGA was not associated with incidental endoscopic findings and the only malignancy presented with an alarm symptom atypical to celiac disease.

Measurement practices of alanine aminotransferase in children: Temporal changes and etiology for increased values.

Data on alanine aminotransferase (ALT) measurement practices and diagnoses associated with increased values are limited. We evaluated these issues by collecting ALT measurements from 1- to 16-year-old patients investigated in 1992-2018 in a tertiary center. Diagnoses were gathered in 2008-2018. Altogether 145,092 measurements from 28,118 children were taken 42% undergoing repeated testing. Testing increased from 21/1000 to 81/1000 children and the prevalence of elevated values fluctuated between 18% and 26%. An increase was seen especially in emergency care and departments of rheumatology, gastroenterology, hemato-oncology, and psychiatry. Common acute causes associated with elevated ALT were infections (45%), hemato-oncologic conditions (17%), and external reasons (13%), whereas autoimmune diseases (28%), psychiatric conditions (14%), and metabolic-dysfunction associated steatotic liver disease (10%) were common chronic causes. In conclusion, ALT testing increased 3.9-fold while the proportion of increased values remained stable, indicating that increased testing was justified. However, in some departments the testing efficiency was low.

Alanine aminotransferase cutoffs for the pediatric fatty liver disease: Major impact of the reference population.

OBJECTIVES AND STUDY: The often-recommended alanine aminotransferase (ALT) cutoffs (girls 21 U/l, boys 25 U/l) are based on a NHANES cohort. A novel concept of metabolic dysfunction associated steatotic liver disease (MASLD) emphasizes the role of ALT. We tested the prevalence of increased ALT and MASLD in children with overweight or obesity applying population-based and NHANES-based cut-offs. METHODS: Six- to seventeen-year-old children underwent data collection in a prospective Physical Activity and Nutrition in Children (PANIC) study. ALT 95th percentiles were calculated from 1167 separate measurements considering various confounders. Test cohort comprised 1044 children with overweight/obesity. RESULTS: ALT values increased at puberty onset (p = 0.031) and correlated negatively with age in girls (r = -0.222, p < 0.001). Particularly overall and central obesity increased ALT, whereas underweight or metabolic abnormalities had smaller effect. After applying the tested exclusions, the age-related ALT 95th percentiles were 24-29 U/l for girls and 29-32 U/l for boys. In 6-8-year-old children with overweight/obesity, the prevalence of increased ALT and MASLD were 21.6% and 2.4% with age-specific PANIC cutoffs. In older children, when NHANES-based cutoffs were used, there was a trend for higher prevalence of increased ALT and MASLD in all age groups for both sexes, reaching significance for increased ALT in 12-16-year-old boys (NHANES 63.5%, 95% confidence interval [CI]: 56.4%-70.0% vs. PANIC 47.1%, 95% CI [40.1%-54.2%]) and 9-11-year-old girls (60.0% [49.4%-69.8%] vs. 31.8% [22.8%-42.3%]), respectively. Increased ALT/MASLD were more common in boys than in girls, and in boys these increased with age, whereas in girls these peaked at age 9-12 years. CONCLUSION: A reference population impacts on the prevalence of increased ALT and MASLD. Considering this help optimizing screening while avoiding unnecessary investigations and surveillance. The prospective part of this study is registered in clinicaltrials.gov; identifier NCT01803776.

Maternal gestational hypertension, smoking and pre-eclampsia are associated with metabolic dysfunction-associated fatty liver disease in overweight offspring.

INTRODUCTION: Due to a steep increase in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD) has also become the most common chronic hepatic condition among children and adolescents. Various maternal and pregnancy-related factors have also been implicated in the development of MAFLD, but human studies remain scarce. MATERIAL AND METHODS: Comprehensive data of 460 overweight or obese children aged 2-16 years were collected and combined with data on selected maternal and pregnancy-related factors for a case-control study. MALFD was defined as alanine aminotransferase >2× upper limit of normal. Children with and without MAFLD were compared regarding to the study variables and multivariable regression analysis was utilized. RESULTS: Median age of the study children was 11.8 (quartiles 9.1-14.2) years; 44% were girls and 17.8% had MAFLD. Children with MAFLD were older (12.7 vs. 11.6 years, p = 0.002), while the groups did not differ age-standardized body mass index (BMI-SDS) or gender. Factors associated with MAFLD in a multivariable model considering also the offspring's present BMI-SDS, sex, and maternal prepregnancy overweight, were child's older age (odds ratio [OR] 1.16, 95% confidence interval [CI]: 1.06-1.28), maternal gestational smoking (OR 2.01, 95% CI: 1.16-3.47), gestational hypertension (OR 3.44, 95% CI: 1.08-11.0) and pre-eclampsia (OR 2.93, 95% CI: 1.15-7.45). There was no significant association between MAFLD and maternal BMI, birth anthropometrics or perinatal complications. CONCLUSIONS: Maternal smoking, gestational hypertension and pre-eclampsia were associated with MAFLD among overweight or obese children. Further prospective studies are needed to verify causal relationships.

Incidence of Pediatric Celiac Disease Varies by Region.

INTRODUCTION: The Environmental Determinants of Diabetes in the Young study follows an HLA risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in CD autoimmunity and CD cumulative incidence for children born between 2004 and 2010. METHODS: Children (n = 6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site. RESULTS: Individual haplogenotype risks for CD autoimmunity and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the United States, the incidence by age 10 years in Colorado was 2.4%. In the model adjusted for HLA, sex, and family history, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared with those in Finland and Germany, respectively. DISCUSSION: There is high regional variability in cumulative incidence of CD, which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.

Prevalence of vomiting and nausea and associated factors after chronic and acute gluten exposure in celiac disease.

BACKGROUND: Vomiting and nausea seem to be relatively specific symptoms related to gluten ingestion in treated celiac disease. However, the overall prevalence and associated factors of these symptoms after chronic gluten exposure at celiac disease diagnosis and acute re-exposure during gluten challenge remain obscure. METHODS: Medical data on 815 adult celiac disease patients were collected at diagnosis from the medical records and through supplementary interviews. An additional 74 patients underwent a three-day (10 g/day) gluten challenge (wheat, barley, rye or a combination of the three grains) while in remission. Prevalence of vomiting/nausea and associated factors were evaluated in both cohorts. A literature review was conducted to summarize earlier studies. RESULTS: Twenty-eight (3%) patients presented with vomiting at diagnosis. They were less often screen-detected and suffered from extra-intestinal symptoms, and had more often abdominal pain (71% vs. 49%, p = 0.021), diarrhea (61% vs. 40%, p = 0.031), weight loss (36% vs. 17%, p = 0.019) and childhood symptoms (61% vs. 33%, p = 0.002) than those without vomiting (n = 787). The groups were comparable in other clinical-demographic data and in genetic, serological, and histological findings. Short-term gluten challenge provoked vomiting/nausea in 14/74 (19%) patients. They consumed gluten-free oats less often than those without these symptoms (64% vs. 92%, p = 0.017), whereas the groups did not differ in clinical-demographic features at diagnosis, presence of comorbidities, duration of gluten-free diet, or in other symptoms or grain used ingested during the challenge. According to the literature, prevalence of vomiting/nausea at celiac disease diagnosis has varied 3-46% and during gluten challenge 13-61%. CONCLUSIONS: In chronic gluten exposure at celiac disease diagnosis, vomiting was associated with other gastrointestinal symptoms and onset of symptoms already in childhood, whereas regular consumption of oats may increase the tolerance against vomiting/nausea after acute re-exposure in treated celiac disease.

Significance of low ferritin without anaemia in screen-detected, adult coeliac disease patients.

BACKGROUND: Low ferritin without anaemia has been linked to adverse health effects. OBJECTIVES: To investigate the prevalence and clinical significance of low ferritin in screen-detected coeliac disease. METHODS: Seventy-six screen-detected coeliac disease patients were enrolled in the prospective collection of comprehensive clinical, laboratory and histological data at diagnosis and after 1-2 years on a gluten-free diet (GFD). All variables were compared between patients with different ferritin levels. RESULTS: At coeliac disease diagnosis, six patients had anaemia. Of the 70 nonanaemic patients, ferritin levels were <15 µg/L in 21%, 15-29 µg/L in 19%, 30-99 µg/L in 36% and ≥100 µg/L in 24%. Those with lower ferritin were more often females, had lower body mass index, haemoglobin and villous height-crypt depth ratio and also had higher intra-epithelial lymphocyte CD3+ levels in duodenal biopsies. The groups did not differ in neurological or gastrointestinal symptoms, health-related quality of life, bone mineral density, liver values, vitamin, albumin or coeliac autoantibody levels or the prevalence of comorbidities. Median ferritin levels increased from 41.5 µg/L to 86.0 µg/L on GFD (p < 0.001). Ferritin remained <30 µg/L in 21% of patients but was not associated with dietary compliance, nor was any correlation between changes in ferritin and quality of life, gastrointestinal symptoms, autoantibody levels or degree of histological damage detected. CONCLUSION: Decreased ferritin is a frequent finding in screen-detected coeliac disease and may not be fully restored on a GFD. However, low ferritin levels are not associated with more severe symptoms or poorer quality of life.

Frequency and clinical significance of histologic upper gastrointestinal tract findings in children with inflammatory bowel disease.

OBJECTIVE: Assessment of the upper gastrointestinal tract (UGI) may enable more personalized treatment strategies in pediatric inflammatory bowel disease (IBD). However, data on the frequency and significance of these findings remain limited. METHODS: Data on 132 pediatric IBD patients with systematic UGI sampling were collected and the baseline characteristics and presence of complications compared between those with and without histological UGI findings. The control group comprised 162 children who received no diagnoses. RESULTS: Seventy-six children had ulcerative colitis (UC), 47 Crohn's disease (CD) and nine IBD unclassified. UGI findings were more common in IBD patients than controls (69.7% vs. 30.9%, respectively, p < .001), particularly in the stomach (62.1% vs. 16.8%; p < .001). Among IBD patients, findings were more common in CD than in UC (80.9% vs. 63.2%; p = .038), particularly in the duodenum (21.3% vs. 2.6%, p = .001). Four patients had UGI granulomas consistent with CD. Hypoalbuminemia (OR 3.22; 95% CI 1.18-8.79) and failure to thrive (2.82; 1.17-6.78) increased the likelihood of UGI findings in IBD. In CD, perianal morbidity was less common in those with than in those without UGI findings (13.2% vs. 44.4%; p = .032) whereas in UC, UGI findings increased the risk for co-morbidities (18.8% vs. 3.6%; p = .059). The long-term outcomes did not differ between patients with or without UGI findings. CONCLUSIONS: Histologic UGI findings were more common in children with IBD than in children with no gastrointestinal diagnoses. In CD, UGI findings were more frequent than in UC, especially in the duodenum. In UC, UGI findings were associated with more complex disease.

Prevalence and Clinical Significance of Helicobacter Pylori-negative Chronic Gastritis in Children.

OBJECTIVES: The clinical significance of Helicobacter pylori-negative chronic gastritis (HPNCG) in children is unclear. We examined this issue in patients who had undergone esophagogastroduodenoscopy with systematic gastric sampling. METHODS: Data of 1178 consecutive children who underwent diagnostic esophagogastroduodenoscopy were collected. Baseline characteristics and long-term outcomes were compared between children with active and inactive HPNCG and those with normal gastric histology. Follow-up data were available for up to 13 years. RESULTS: Altogether 24 (2.0%) children had active and 235 (19.9%) inactive HPNCG, 27 (2.3%) were Hpylori-positive, 46 (3.9%) had other gastric pathology, and 846 (71.8%) normal histology. Diarrhea (31.3% vs 25.1%, P  = 0.033), poor growth (23.6% vs 14.7%, P  < 0.001), bloody stools (13.9% vs 7.2%, P < 0.001), anemia (46.5% vs 23.4%, P < 0.001), hypersedimentation (39.7% vs 21.4%, P < 0.001), hypoalbuminemia (40.4% vs 16.2%, P < 0.001), and elevated fecal calprotectin (62.4% vs 31.5%, P < 0.001) were more common and heartburn (13.9% vs 22.9%, P = 0.002) less common in the HPNCG group than in the controls. Both active (OR 3.64,95% CI 1.35-9.82) andinactive (2.98, 2.18-4.08) HPNCG predicted a diagnosis in the initial investigations. Crohn disease (41.7%) was the most common diagnosis in active HPNCG and celiac disease (37.4%) in inactive HPNCG. During follow-up, 7 (9.9%) of the 71 initially nondiagnosed HPNCG children received a diagnosis. CONCLUSIONS: HPNCG is a frequent finding in children undergoing EGD, the active form being associated especially with Crohn disease and the inactive with celiac disease. The long-term prognosis of patients with HPNCG who do not receive an initial diagnosis is good.

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.

Clustering based approach for population level identification of condition-associated T-cell receptor ß-chain CDR3 sequences.

BACKGROUND: Deep immune receptor sequencing, RepSeq, provides unprecedented opportunities for identifying and studying condition-associated T-cell clonotypes, represented by T-cell receptor (TCR) CDR3 sequences. However, due to the immense diversity of the immune repertoire, identification of condition relevant TCR CDR3s from total repertoires has mostly been limited to either "public" CDR3 sequences or to comparisons of CDR3 frequencies observed in a single individual. A methodology for the identification of condition-associated TCR CDR3s by direct population level comparison of RepSeq samples is currently lacking. RESULTS: We present a method for direct population level comparison of RepSeq samples using immune repertoire sub-units (or sub-repertoires) that are shared across individuals. The method first performs unsupervised clustering of CDR3s within each sample. It then finds matching clusters across samples, called immune sub-repertoires, and performs statistical differential abundance testing at the level of the identified sub-repertoires. It finally ranks CDR3s in differentially abundant sub-repertoires for relevance to the condition. We applied the method on total TCR CDR3ß RepSeq datasets of celiac disease patients, as well as on public datasets of yellow fever vaccination. The method successfully identified celiac disease associated CDR3ß sequences, as evidenced by considerable agreement of TRBV-gene and positional amino acid usage patterns in the detected CDR3ß sequences with previously known CDR3ßs specific to gluten in celiac disease. It also successfully recovered significantly high numbers of previously known CDR3ß sequences relevant to each condition than would be expected by chance. CONCLUSION: We conclude that immune sub-repertoires of similar immuno-genomic features shared across unrelated individuals can serve as viable units of immune repertoire comparison, serving as proxy for identification of condition-associated CDR3s.

Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes.

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (PT) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (PEMP2 ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (PT = 0.2, PEMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.

Nonbiopsy Approach for Celiac Disease Is Accurate When Using Exact Duodenal Histomorphometry: Prospective Study in 2 Countries.

GOALS: To test the accuracy of serology-based criteria for diagnosing celiac disease utilizing quantitative histomorphometry. BACKGROUND: The revised European pediatric guidelines allow noninvasive celiac disease diagnosis for a subgroup of children. However, in some of the studies on this issue, the positive predictive value (PPV) of serology has remained suboptimal, possibly because of challenges of histopathology as the reference standard. STUDY: Prospectively enrolled children with transglutaminase 2 antibodies (TGA) above the upper limit of normal (ULN) underwent blood sampling and duodenal biopsy in Finland and Romania. Those with TGA ≥10× ULN, positive endomysium antibodies (EmA), and disease-associated genetics were considered to fulfill triple criteria for celiac disease. Initial histopathologic analysis was conducted using grouped classification, whereupon centralized morphometry was performed. RESULTS: Altogether 88 (54%) children were triple positive. In local evaluation, 99% of triple-positive children and 73% of children with TGA <10× ULN had celiac disease. These figures increased to 100% and 85% after more precise morphometric analysis. Triple-positive children had more anemia and higher median EmA and liver enzyme values than those with TGA<10× ULN; the groups were comparable in other clinical features and laboratory parameters. CONCLUSIONS: When applied as recommended, the nonbiopsy strategy had already yielded excellent PPV regardless of the site of diagnosis or clinical presentation in the local analysis. PPV further increased to 100% with standardized duodenal morphometry.

Impact of diagnostic delay to the clinical presentation and associated factors in pediatric inflammatory bowel disease: a retrospective study.

BACKGROUND: Undelayed diagnosis is thought to be a major determinant for good prognosis in pediatric inflammatory bowel disease (PIBD). However, factors predicting diagnostic delay and the consequences of this remain poorly defined. We investigated these issues in a well-defined cohort of PIBD patients. METHODS: Comprehensive electronic data were collected from 136 PIBD patients retrospectively. Diagnostic delay was further classified into < 6 and ≥ 6 months, and < 12 and ≥ 12 months. Logistic regression was used to calculate whether the delay was associated with clinical features and/or risk of complications and co-morbidities at diagnosis. RESULTS: The median age of patients was 12.4 years and 43.4% were females. Altogether 35.5% had Crohn´s disease (CD), 59.1% ulcerative colitis (UC) and 6.6% IBD undefined (IBD-U). The median delay before diagnosis was 5.0 months in all, 6.6 months in CD, 4.1 months in UC, and 9.8 months in IBD-U (UC vs. CD, p = 0.010). In all but IBD-U most of the delay occurred before tertiary center referral. Abdominal pain predicted a delay > 6 months in all PIBD (OR 2.07, 95% CI 1.00-4.31) and in UC patients (3.15, 1.14-8.7), while bloody stools predicted a shorter delay in all PIBD (0.28, 0.14-0.59) patients and in CD (0.10, 0.03-0.41) patients. A delay > 6 months was associated with a higher frequency of complications (2.28, 1.01-5.19). CONCLUSIONS: Delay occurred mostly before specialist consultation, was longer in children presenting with abdominal pain and in CD and was associated with risk of complications. These findings emphasize the roles of active case-finding and prompt diagnostic evaluations.

Differences Between Familial and Sporadic Celiac Disease.

BACKGROUND: It is not known if genetic background, characteristics at diagnosis, physical and psychological well-being, and adherence to a gluten-free diet are comparable between patients with familial or sporadic celiac disease. These issues were investigated in a follow-up study. METHODS: Altogether 1064 patients were analyzed for celiac disease-associated serology, predisposing HLA-DQ, and non-HLA genotypes. Medical data were collected from patient records and supplementary interviews. Current symptoms and quality of life were further evaluated with the Gastrointestinal Symptom Rating Scale (GSRS), the Psychological General Well-Being questionnaire (PGWB), and Short Form 36 (SF-36) questionnaires. RESULTS: Familial and sporadic groups differed (P < 0.001) in the reason for diagnosis and clinical presentation at diagnosis, familial patients being more often screen-detected (26% vs. 2%, P < 0.001) and having less often gastrointestinal (49% vs. 69%) and severe symptoms (47% vs. 65%). The groups were comparable in terms of histological damage, frequency of malabsorption, comorbidities, childhood diagnoses, and short-term treatment response. At the time of the study, familial cases reported fewer symptoms (21% vs. 30%, P = 0.004) and lower prevalence of all (78% vs. 86%, P = 0.007), neurological (10% vs. 15%, P = 0.013), and dermatological (9% vs. 17%, P = 0.001) comorbidities. Dietary adherence and GSRS scores were comparable, but familial cases had better quality of life according to PGWB and SF-36. High-risk genotype HLA-DQ2.5/DQ2.5 was more frequent among familial cases, and four non-HLA SNPs were associated with familial celiac disease. CONCLUSIONS: Despite the greater proportion of high-risk genotypes, familial cases had milder symptoms at presentation than did sporadic cases. Worse experience of symptoms and poorer quality of life in sporadic disease indicate a need for intensified support.

Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study.

OBJECTIVE: Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. However, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (CDA) in genetically predisposed children. DESIGN: The Environmental Determinants of Diabetes in the Young study prospectively followed children carrying the HLA risk haplotypes DQ2 and/or DQ8 and constructed a nested case-control design. From this design, 83 CDA case-control pairs were identified. Median age of CDA was 31 months. Stool samples collected monthly up to the age of 2 years were analysed for virome composition by Illumina next-generation sequencing followed by comprehensive computational virus profiling. RESULTS: The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for CDA. In addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake. CONCLUSIONS: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA.

Diagnostic findings and long-term prognosis in children with anemia undergoing GI endoscopies.

BACKGROUND AND AIMS: Intestinal diseases are regarded as a common cause of anemia, but the diagnostic outcomes of children with anemia undergoing endoscopic investigations are unclear. We investigated this issue in a large cohort of children. METHODS: Indications for and findings of consecutive gastrointestinal (GI) endoscopies were collected. Clinical presentation and diagnostic outcomes were compared between anemic and nonanemic patients and between anemic patients with and without a diagnosis. Diagnoses received during follow-up were collected. RESULTS: Of 2395 consecutive endoscopies, 251 children with and 613 children without anemia had undergone either diagnostic esophagogastroduodenoscopy (EGD) (51.4% and 51.4%, respectively), colonoscopy (4.0% and 11.4%), or both (45.8% and 37.8%). Children with anemia more often received diagnoses (72.9% vs 39.3%; odds ratio [OR], 4.18; 95% confidence interval [CI], 3.03-5.77), particularly of celiac disease (26.3% vs 15.5%, P < .001) and of inflammatory bowel disease (31.1% vs 9.1%, P < .001), than did nonanemic children. The diagnosis in anemic patients was predicted by age 5 to 12 years (OR, 3.52; 95% CI, 1.27-9.75), presence of diarrhea (OR, 2.04; 95% CI, 1.07-3.90), melena/hematochezia (OR, 2.40; 95% CI, 1.17-4.92), poor growth (OR, 3.94; 95% CI, 1.70-9.15), positive celiac serology (OR, 11.81; 95% CI, 3.47-40.12), high calprotectin (OR, 12.86; 95% CI, 4.00-41.32), hypersedimentation (OR, 2.65; 95% CI, 1.29-5.44), and hypoalbuminemia (OR, 5.05; 95% CI, 1.56-16.34). Thirty children with anemia (12.0%) had no GI symptoms, and 22 of them (73.3%) were given diagnoses at the time of the endoscopies. All 22 had additional laboratory abnormalities, whereas these were present in only 2 of 8 undiagnosed children. None of them was diagnosed later in the follow-up of up to 11 years, in contrast to 4 (6.7%) of all anemic and 33 (8.9%) of all nonanemic patients. CONCLUSIONS: Anemia increased the probability of being given a diagnosis, emphasizing its importance as an alarm symptom. However, endoscopies in anemic patients without additional symptoms or laboratory abnormalities seldom improved the diagnostic yield.

Severity of Villous Atrophy at Diagnosis in Childhood Does Not Predict Long-term Outcomes in Celiac Disease.

OBJECTIVES: Current pediatric guidelines allow noninvasive diagnosis of celiac disease in selected children. We investigated in a large cohort study whether the severity of villous atrophy at diagnosis is associated with clinical characteristics or long-term health outcomes, thus having a prognostic significance. METHODS: Comprehensive medical data on 906 children with celiac disease were analyzed. Long-term health outcomes of 503 adult patients diagnosed in childhood were moreover assessed with a specific study questionnaire and validated Gastrointestinal Symptom Rating Scale (GSRS) and Psychological General Well-Being (PGWB) questionnaires. Patients were classified into 3 groups according to the severity of villous atrophy at diagnosis, and all variables were compared. RESULTS: Altogether 34% of the patients had partial, 40% subtotal, and 26% total villous atrophy. Children with milder lesions were diagnosed more recently (median year 2007 vs 2006 vs 2001, respectively, P < 0.001), more often by screening (30% vs 25% vs 17%, P < 0.001) and they suffered less often from anemia (16% vs 21% vs 32%, P < 0.001) and growth disturbances (22% vs 36% vs 54%, P < 0.001) and had lower transglutaminase-2 antibody levels (median 64 U/L vs 120 U/L vs 120 U/L, P < 0.001). There was no difference in other disease features.Altogether 212 adults diagnosed in childhood completed the questionnaires. Severity of villous atrophy at childhood diagnosis did not predict presence of complications or comorbidities, persistent symptoms, and self-perceived health, quality of life or adherence to a gluten-free diet in adulthood. CONCLUSION: Presence of advanced villous atrophy at diagnosis is associated with more severe clinical characteristics but not with poorer long-term health and treatment outcomes.

European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020.

OBJECTIVES: The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. METHODS: Literature databases and other sources of information were searched for studies that could inform on 10 formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. RESULTS: Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable, an IgG-based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10× ULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10× ULN at least 4 biopsies from the distal duodenum and at least 1 from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. CONCLUSIONS: CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.