One-Year Outcomes Among Children Identified With Celiac Disease Through a Mass Screening Program.

BACKGROUND & AIMS: Celiac disease (CD) mass screening remains controversial in part because of a paucity of data to support its benefit. The Autoimmunity Screening for Kids study is a mass screening study for pediatric CD and type 1 diabetes in Colorado. METHODS: This study prospectively follows up children ages 1 to 17 years who screened positive for tissue transglutaminase IgA autoantibodies in the Autoimmunity Screening for Kids study subsequently referred for diagnostic evaluation. Children diagnosed with CD by biopsy or serologic criteria were included in this study. Evaluation at baseline and 12 month follow-up evaluation included demographics, laboratory studies, symptoms, health-related quality of life, anxiety/depression, and gluten-free diet adherence. Paired Student t test, chi-square, and Wilcoxon sign rank tests compared baseline and follow-up data. For symptom scores, odds of improvement were assessed. RESULTS: Of the 52 children with CD enrolled, 42 children completed 12-month follow-up evaluation. On the symptom questionnaire completed at diagnostic evaluation, 38 of 42 children reported 1 or more symptoms. CD mean symptom severity and frequency scores improved from baseline to follow-up evaluation (P < .001). Reported health-related quality of life scores improved among caregivers (P = .002). There was no significant change in reported anxiety or depression. Iron deficiency without anemia was common at baseline (21 of 24 children; 87.5%) and normalized at follow-up evaluation (11 of 21 children; 52.3%). Twenty-six of 28 families reported good or excellent gluten-free diet adherence. CONCLUSIONS: This novel study of children with CD identified through a mass screening program demonstrated improvement in symptoms, quality of life, and iron deficiency after 1 year follow-up evaluation. This demonstrates that there may be benefit to CD mass screening.

Gluten Intake and Risk of Celiac Disease: Long-Term Follow-up of an At-Risk Birth Cohort.

OBJECTIVES: To determine the association between the amount of gluten intake in childhood and later celiac disease (CD), for which data are currently scarce. METHODS: The prospective Diabetes Autoimmunity Study in the Young cohort includes 1875 at-risk children with annual estimates of gluten intake (grams/d) from age 1 year. From 1993 through January 2017, 161 children, using repeated tissue transglutaminase (tTGA) screening, were identified with CD autoimmunity (CDA) and persistent tTGA positivity; of these children, 85 fulfilled CD criteria of biopsy-verified histopathology or persistently high tTGA levels. Cox regression, modeling gluten intake between ages 1 and 2 years (i.e., in 1-year-olds), and joint modeling of cumulative gluten intake throughout childhood were used to estimate hazard ratios adjusted for confounders (aHR). RESULTS: Children in the highest third of gluten intake between the ages of 1 and 2 years had a 2-fold greater hazard of CDA (aHR 2.17; 95% confidence interval [CI], 1.22-3.88; P value = 0.01) and CD (aHR 1.96; 95% CI, 0.90-4.24; P value = 0.09) than those in the lowest third. The risk of developing CDA increased by 5% per daily gram increase in gluten intake (aHR 1.05; 95% CI, 1.00-1.09; P value = 0.04) in 1-year-olds. The association between gluten intake in 1-year-olds and later CDA or CD did not differ by the child's human leukocyte antigen genotype. The incidence of CD increased with increased cumulative gluten intake throughout childhood (e.g., aHR 1.15 per SD increase in cumulative gluten intake at age 6; 95% CI, 1.00-1.32; P value = 0.04). DISCUSSION: Gluten intake in 1-year-olds is associated with the future onset of CDA and CD in children at risk for the disease.

High Incidence of Celiac Disease in a Long-term Study of Adolescents With Susceptibility Genotypes.

BACKGROUND & AIMS: Little is known about the incidence of celiac disease in the general population of children in the United States. We aimed to estimate the cumulative incidence of celiac disease in adolescents born in the Denver metropolitan area. METHODS: We collected data on HLA-DR, DQ genotypes of 31,766 infants, born from 1993 through 2004 at St. Joseph's Hospital in Denver, from the Diabetes Autoimmunity Study in the Young. Subjects with susceptibility genotypes for celiac disease and type 1 diabetes were followed up for up to 20 years for development of tissue transglutaminase autoantibodies (tTGA). Outcomes were the development of celiac disease autoimmunity (CDA) or celiac disease. CDA was defined as persistence of tTGA for at least 3 months or development of celiac disease. Celiac disease was defined based on detection of Marsh 2 or greater lesions in biopsy specimens or persistent high levels of tTGA. For each genotype, the cumulative incidence of CDA and celiac disease were determined. To estimate the cumulative incidence in the Denver general population, outcomes by each genotype were weighted according to the frequency of each of these genotypes in the general population. RESULTS: Of 1339 subjects followed up, 66 developed CDA and met criteria for celiac disease and 46 developed only CDA. Seropositivity for tTGA resolved spontaneously, without treatment, in 21 of the 46 subjects with only CDA (46%). The estimated cumulative incidence for CDA in the Denver general population at 5, 10, and 15 years of age was 2.4%, 4.3%, and 5.1%, respectively, and incidence values for celiac disease were 1.6%, 2.8%, and 3.1%, respectively. CONCLUSIONS: In a 20-year prospective study of 1339 children with genetic risk factors for celiac disease, we found the cumulative incidence of CDA and celiac disease to be high within the first 10 years. Although more than 5% of children may experience a period of CDA, not all children develop celiac disease or require gluten-free diets.

Higher Sensitivity and Earlier Identification of Celiac Disease Autoimmunity by a Nonradioactive Assay for Transglutaminase Autoantibodies.

Higher sensitive transglutaminase autoantibody (TGA) assay will detect the onset of celiac disease (CD) autoimmunity earlier. In developing a nonradioactive assay for TGA, we utilized electrochemiluminescence (ECL) technology and compared it to a high-performance radioimmunoassay (RIA) currently being used to screen patients with type 1 diabetes (T1D) and genetically at-risk individuals for CD. We selected 183 T1D patients with 60 patients having received biopsy and analyzed 396 sequential samples from 73 young children longitudinally followed up with TGA seroconversion, with 27 undergoing biopsy. In addition, 112 age-matched healthy control subjects were included in the study. With the 99th percentile of specificity, the ECL assay detected significantly more TGA positivity among patients with T1D (133/183) than RIA (114/183) and more of the sequential samples (34%) from 73 children than RIA (18%). The TGA assay performed by ECL was positive in all 59 subjects with villous atrophy. Among 73 longitudinally followed up children, ECL assay had earlier detection of TGA on 34 children by a mean of 2.5 years. In conclusion, the new TGA assay by ECL has a higher sensitivity than the current RIA assay and may better predict the onset of CD.

Comparison of Metabolic Outcomes in Children Diagnosed with Type 1 Diabetes Through Research Screening (Diabetes Autoimmunity Study in the Young [DAISY]) Versus in the Community.

BACKGROUND: Children with positive islet autoantibodies monitored prospectively avoid metabolic decompensation at type 1 diabetes (T1D) diagnosis. However, the effects of early diagnosis and treatment on preservation of insulin secretion and long-term metabolic control are unknown. We compared characteristics of children detected through research screening (Diabetes Autoimmunity Study in the Young [DAISY]) versus community controls at baseline and, in a subset, 6- and 12-month metabolic outcomes. MATERIALS AND METHODS: This was a case-control study comparing DAISY children with T1D to children diagnosed in the general community. All participants underwent mixed-meal tolerance testing; a subset wore a continuous glucose monitoring (CGM) device. Fasting and stimulated C-peptide levels, insulin dose-adjusted hemoglobin A1c (IDAA1c), and CGM variables were compared. RESULTS: Children (21 DAISY, 21 community) were enrolled and matched by age, time of diagnosis, and diabetes duration; 18 were enrolled within 2 months and 24 within 2.5 years on average from diagnosis. In the overall group and the subgroup of participants enrolled 2.5 years from diagnosis, there were no IDAA1c or C-peptide differences between DAISY versus community children. The subgroup of DAISY versus community children enrolled near diagnosis, however, had lower baseline hemoglobin A1c (6.5±1.4% vs. 9.2±2.9%; P=0.0007) and IDAA1c (7.4±2.1% vs. 11.2±3.5%; P=0.04) and higher stimulated C-peptide (2.5±0.5 vs. 1.6±0.2 ng/mL; P=0.02). In this subgroup, IDAA1c differences persisted at 6 months but not at 1 year. CGM analyses revealed lower minimum overnight glycemia in community children (72 vs. 119 mg/dL; P=0.01). CONCLUSIONS: Favorable patterns of IDAA1c and C-peptide seen in research-screened versus community-diagnosed children with T1D within 2 months of diagnosis are no longer apparent 1 year from diagnosis.

Celiac autoimmunity in children with type 1 diabetes: a two-year follow-up.

OBJECTIVE: To determine the benefits of screening for celiac autoimmunity via immunoglobulin A transglutaminase autoantibodies (TG) in children with type 1 diabetes (T1D). STUDY DESIGN: We followed up 79 screening-identified TG+ and 56 matched TG- children with T1D for 2 years to evaluate growth, bone mineral density, nutritional status, and diabetes control. TG+ subjects self-selected to gluten-free or gluten-containing diet. RESULTS: Of the initial cohort, 80% were available for reexamination after 2 years. TG+ subjects had consistently lower weight z-scores and higher urine N-telopeptides than TG- subjects, but similar measures of bone density and diabetes outcomes. TG+ children who remained on a gluten-containing diet had lower insulin-like growth factor binding protein 3 z-scores compared with TG+ subjects who reported following a gluten-free diet. Children who continued with high TG index throughout the study had lower bone mineral density z-scores, ferritin, and vitamin D 25OH levels, compared with the TG- group. CONCLUSIONS: No significant adverse outcomes were identified in children with T1D with screening-identified TG+ who delay therapy with a gluten-free diet for 2 years. Children with persistently high levels of TG may be at greater risk. The optimal timing of screening and treatment for celiac disease in children with T1D requires further investigation.

Natural history of antibodies to deamidated gliadin peptides and transglutaminase in early childhood celiac disease.

INTRODUCTION: Gliadin proteins play a key role in the pathogenesis of celiac disease; however, as a screen for celiac disease, anti-gliadin antibody testing has been replaced by the more sensitive and specific serological assays for transglutaminase autoantibodies (TGAA). A new generation of anti-gliadin antibody assays has been developed to detect synthetic, deamidated homologous gliadin peptides (DGP) with high sensitivity and specificity. METHODS: Sera were collected prospectively from children with an increased risk for celiac disease as part of an ongoing study at Denver, and studied for the development of celiac autoimmunity. We investigated the high-performance DGP antibody assay in 50 TGAA-positive children both before the development of celiac autoimmunity and following the institution of a gluten-free diet to determine the relationship of DGP antibodies to TGAA. TGAA were measured by an in-house radioassay. RESULTS: DGP antibodies and TGAA parallel each other over the period of years children were studied. DGP antibodies resolved sooner than TGAA in subjects on a gluten-free diet. DGP antibodies appeared earlier than TGAA in 9 children. CONCLUSIONS: Measuring DGP antibodies may be more useful than TGAA in monitoring children on a gluten-free diet. DGP antibodies can precede the appearance of TGAA in some at-risk children.

Impact of celiac autoimmunity on children with type 1 diabetes.

OBJECTIVE: Children with type 1 diabetes (T1DM) are at increased risk for celiac disease (CD); however, the benefits of screening for IgA tissue transglutaminase autoantibodies (TG), a marker for CD, are unclear. STUDY DESIGN: We compared 71 screening-identified TG+ with 63 matched TG- children with TIDM. Growth, bone density, and diabetes control measures were obtained. RESULTS: The group was 10 +/- 3 years of age, 46% male, with TIDM for 4 +/- 3 years. Z scores for weight (0.3 +/- 1 vs 0.7 +/- 0.8, P = .024), body mass index (BMI) (0.3 +/- 0.9 vs 0.8 +/- -0.8, P = .005), and midarm circumference (0.3 +/- 1.1 vs 0.6 +/- 0.9, P = .031) were lower in the TG+ group. Bone mineral density and diabetes control measures were similar. When limiting the analysis to the 35 TG+ subjects with biopsy changes of CD, the BMI Z score was lower than the control group (0.4 +/- 0.9 vs 0.7 +/- 0.7, P = .05). CONCLUSIONS: In children with TIDM, screening-identified evidence of CD is associated with altered body composition, but not bone mineral density or diabetes control. Further study is needed to determine the benefit of early diagnosis and treatment of CD in TIDM children.

Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study.

OBJECTIVE: Few studies have assessed the role of specific gastrointestinal infections in celiac disease. We investigated whether increased frequency of rotavirus infection, a common cause of gastrointestinal infection and inflammation, predicts increased risk of celiac disease autoimmunity. METHODS: A cohort of 1,931 children from the Denver metropolitan area who carried celiac disease human leukocyte antigen (HLA) risk alleles were followed from infancy for development of celiac disease autoimmunity, defined as positivity at two or more subsequent clinic visits for tissue transglutaminase (tTG) autoantibodies measured using a radioimmunoassay with human recombinant tTG. Blood samples were obtained at ages 9, 15, and 24 months, and annually thereafter. Rotavirus antibodies were assayed using an indirect enzyme immunoassay in serial serum samples from each case and two matched controls. Frequency of infections were estimated by the number of increases (> 2 assay coefficient of variation) in rotavirus antibody between clinic visits. RESULTS: Fifty-four cases developed celiac disease autoimmunity at a median age of 4.4 yr. Thirty-six had an intestinal biopsy, of which 27 (75%) were positive for celiac disease. Frequent rotavirus infections predicted a higher risk of celiac disease autoimmunity (compared with zero infections, rate ratio 1.94, 95% confidence interval [CI] 0.39-9.56, for one infection and rate ratio 3.76, 95% CI 0.76-18.7, for > or = 2 infections, rate ratio for trend per increase in number of infections = 1.94, 95% CI 1.04-3.61, p = 0.037). The result was similar after adjustment for gender, ethnic group, maternal education, breast-feeding, day-care attendance, number of siblings, season of birth, and number of HLA DR3-DQ2 haplotypes. CONCLUSIONS: This prospective study provides the first indication that a high frequency of rotavirus infections may increase the risk of celiac disease autoimmunity in childhood in genetically predisposed individuals.

Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.

CONTEXT: While gluten ingestion is responsible for the signs and symptoms of celiac disease, it is not known what factors are associated with initial appearance of the disease. OBJECTIVE: To examine whether the timing of gluten exposure in the infant diet was associated with the development of celiac disease autoimmunity (CDA). DESIGN, SETTING, AND PATIENTS: Prospective observational study conducted in Denver, Colo, from 1994-2004 of 1560 children at increased risk for celiac disease or type 1 diabetes, as defined by possession of either HLA-DR3 or DR4 alleles, or having a first-degree relative with type 1 diabetes. The mean follow-up was 4.8 years. MAIN OUTCOME MEASURE: Risk of CDA defined as being positive for tissue transglutaminase (tTG) autoantibody on 2 or more consecutive visits or being positive for tTG once and having a positive small bowel biopsy for celiac disease, by timing of introduction of gluten-containing foods into the diet. RESULTS: Fifty-one children developed CDA. Findings adjusted for HLA-DR3 status indicated that children exposed to foods containing wheat, barley, or rye (gluten-containing foods) in the first 3 months of life (3 [6%] CDA positive vs 40 [3%] CDA negative) had a 5-fold increased risk of CDA compared with children exposed to gluten-containing foods at 4 to 6 months (12 [23%] CDA positive vs 574 [38%] CDA negative) (hazard ratio [HR], 5.17; 95% confidence interval [CI], 1.44-18.57). Children not exposed to gluten until the seventh month or later (36 [71%] CDA positive vs 895 [59%] CDA negative) had a marginally increased risk of CDA compared with those exposed at 4 to 6 months (HR, 1.87; 95% CI, 0.97-3.60). After restricting our case group to only the 25 CDA-positive children who had biopsy-diagnosed celiac disease, initial exposure to wheat, barley, or rye in the first 3 months (3 [12%] CDA positive vs 40 [3%] CDA negative) or in the seventh month or later (19 [76%] CDA positive vs 912 [59%] CDA negative) significantly increased risk of CDA compared with exposure at 4 to 6 months (3 [12%] CDA positive vs 583 [38%] CDA negative) (HR, 22.97; 95% CI, 4.55-115.93; P = .001; and HR, 3.98; 95% CI, 1.18-13.46; P = .04, respectively). CONCLUSION: Timing of introduction of gluten into the infant diet is associated with the appearance of CDA in children at increased risk for the disease.

Clinical features of children with screening-identified evidence of celiac disease.

OBJECTIVE: At-risk groups commonly undergo screening for autoantibodies associated with celiac disease (CD). However, the clinical significance of a positive test remains uncertain. The objective of this study was to evaluate growth and clinical features of children who test positive for an autoantibody associated with CD. METHODS: A case-control study of Denver area healthy infants and young children with and without CD autoantibodies was conducted. A cohort of HLA-characterized children were followed prospectively since birth for the development of immunoglobulin A antitissue transglutaminase autoantibodies (TG). Clinical evaluation, questionnaire, blood draw, and small bowel biopsy were performed. Growth and nutrition and frequency of positive responses were measured. RESULTS: Compared with 100 age- and gender-matched TG-negative controls, 18 TG-positive children, 5.5 +/- 0.5 years of age, had a greater number of symptoms and lower z scores for weight-for-height and for body mass index. Responses that were independently associated with TG-positive status were irritability/lethargy, abdominal distention/gas, and difficulty with weight gain. CONCLUSIONS: Screening-identified TG-positive children demonstrate mild alterations in growth and nutrition and report more symptoms than control subjects. Additional study is needed on the benefit and risk of identifying CD in at-risk groups.

A prospective study of the incidence of childhood celiac disease.

OBJECTIVES: To estimate the frequency of celiac disease (CD) in children in the general population of Denver, Colorado. STUDY DESIGN: From 22,346 newborns characterized as expressing 0, 1, or 2 HLA-DR3(DQB1*0201) alleles, 987 were selected for a prospective stratified cohort study. Participants were followed for as long as 7 years with serial testing for serum IgA anti-transglutaminase antibodies and for evidence of CD (intestinal mucosal changes or persistent seropositivity). RESULTS: Of 40 children with at least one positive serologic test, 19 had evidence of CD (10 by biopsy, 9 by persistent seropositivity). Those expressing 0, 1, or 2 HLA-DR3 alleles had, respectively, 0.3% (95% CI, 0.0-2.7), 3.4% (3.0-11.7), and 3.2% (1.0-11.0) risk for evidence of CD by age 5 years. The adjusted risk estimate for evidence of CD by age 5 years for the Denver general population was 0.9% (0.4-2.0), or 1 in 104 (1:49-221). After adjusting for number of HLA-DR3 alleles expressed, risk was higher in females: RR=3.34 (1.00-10.9, P=.048). Evidence of CD was not observed before age 2.6 years. CONCLUSIONS: Celiac disease may affect 0.9% of Denver children by 5 years of age. Children positive for the HLA-DR3 allele and females appear to be at increased risk.