Iman Taki

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 ≥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.

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.

A Report on the International Transglutaminase Autoantibody Workshop for Celiac Disease

OBJECTIVES:Measurement of transglutaminase autoantibodies (TGAA) is considered to be the most efficient single serologic test for celiac disease (CD) by the American Gastroenterological Association Institute. We hypothesized that a large international collaborative effort toward improving and standardizing TGAA measurement is both feasible and necessary. The primary aim of this workshop is to compare TGAA assays among various research and clinical laboratories to examine assay concordance and improve (and eventually standardize) the TGAA assay.METHODS:A total of 20 laboratories (5 commercial laboratories, 15 research and clinical laboratories) participated that included enzyme-linked immunosorbent assay (ELISA) and radiobinding assays. A total of 150 serum samples were distributed to each laboratory, with each laboratory receiving an equal aliquot that was coded and blinded, composed of 100 healthy control sera and 50 CD sera.RESULTS:Laboratory sensitivity ranged from 69% to 93% and specificity ranged from 96% to 100%. By receiver operator characteristic analysis, the area under the curve (C index) ranged from 0.9488 to 0.9904. When analyzing for linear correlation, r-squared was as high as 0.8882 but as low as 0.4244 for the celiac samples between different laboratories performing ELISA.CONCLUSIONS:This transglutaminase autoantibody workshop allows for larger-scale international participation for the purposes of improving and eventually standardizing the TGAA assay with subsequent workshops.

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.

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.

Early Hyperglycemia Detected by Continuous Glucose Monitoring in Children at Risk for Type 1 Diabetes

OBJECTIVE We explore continuous glucose monitoring (CGM) as a new approach to defining early hyperglycemia and diagnosing type 1 diabetes in children with positive islet autoantibodies (Ab+). RESEARCH DESIGN AND METHODS Fourteen Ab+ children, free of signs or symptoms of diabetes, and nine antibody-negative (Ab−) subjects, followed by the Diabetes Autoimmunity Study in the Young, were asked to wear a Dexcom SEVEN CGM. RESULTS The Ab+ subjects showed more hyperglycemia, with 18% time spent above 140 mg/dL, compared with 9% in Ab− subjects (P = 0.04). Their average maximum daytime glucose value was higher, and they had increased glycemic variability. The mean HbA1c in the Ab+ subjects was 5.5% (37 mmol/mol). Among Ab+ subjects, ≥18–20% CGM time spent above 140 mg/dL seems to predict progression to diabetes. CONCLUSIONS CGM can detect early hyperglycemia in Ab+ children who are at high risk for progression to diabetes. Proposed CGM predictors of progression to diabetes require further validation.

Reduced Bone Mineral Density Is Associated with Celiac Disease Autoimmunity in Children with Type 1 Diabetes.

OBJECTIVE To evaluate the association between bone mineral density (BMD), glycemic control (hemoglobin A1c [HbA1c]), and celiac autoimmunity in children with type 1 diabetes mellitus (T1D) and in an appropriate control population. STUDY DESIGN BMD was assessed cross-sectionally in 252 children with T1D (123 positive for anti-tissue transglutaminase antibody [tTGA] and 129 matched children who were negative for tTGA). In addition, BMD was assessed in 141 children without diabetes who carried T1D-associated HLD-DR, DQ genotypes (71 positive for tTGA and 70 negative). RESULTS Children with T1D who were positive for tTGA had significantly worse BMD L1-L4 z-score compared with children with T1D who were negative for tTGA (-0.45 ± 1.22 vs 0.09 ± 1.10, P = .0003). No differences in growth measures, urine N-telopeptides, 25-hydroxyvitamin D, ferritin, thyroid stimulating hormone, or HbA1c were found. However, both higher HbA1c (β = -1.25 ± 0.85, P = .0016) and tTGA (β = -0.13 ± 0.05, P = .0056) were significant and independent predictors of lower BMD in multivariate analyses. No differences in BMD or other variables measured were found between children without diabetes who were positive vs negative for tTGA. CONCLUSIONS The results suggest a synergistic effect of hyperglycemia and celiac autoimmunity on low BMD.

Antibodies to the wheat storage globulin Glo-3A in children before and at diagnosis of celiac disease

Objective: Celiac disease (CD) is an autoimmune disease triggered by exposure to gluten-containing foods. IgA autoantibodies to tissue transglutaminase (TTG) are elevated in CD, but little is known about the gastrointestinal state before the appearance of TTG. Antibodies to wheat storage globulin Glo-3A have been studied in type 1 diabetes, and may be a marker of altered mucosal barrier and/or immune function. In the present study, we investigated antibody responses to Glo-3A in CD. Patients and Methods: In the Diabetes Autoimmunity Study in the Young, children were studied prospectively from birth for the appearance of TTG and CD. Fifty cases of CD were frequency matched with 50 controls on age (of TTG seroconversion in the case), sex, ethnicity, presence of a first-degree relative with type 1 diabetes mellitus, and human leukocyte antigen -DR3 genotype. In cases and controls, IgG antibodies to Glo-3A were analyzed in a blinded manner in the sample collected at the time of seroconversion to TTG positivity (or the matched sample in controls) and in all of the previous samples since birth (mean 4.5 samples). The association between Glo-3A antibody levels and CD case status was explored using t tests at the TTG-positive visit and when Glo-3A levels were highest, and mixed modeling to describe Glo-3A over time. Results: At the time of first elevated TTG (mean 4.9 years), patients with CD had higher Glo-3A antibody levels than controls (13.3 ± 17.2 vs 7.6 ± 11.7, P = 0.005). In both cases and controls, Glo-3A antibodies appear to peak at a mean age of 2.9 years, before mean age of initial TTG seroconversion. The peak Glo-3A antibody levels were higher in cases than controls (25.5 ± 21.8 vs 14.9 ± 18.3 P = 0.0007). Using mixed modeling to account for multiple visits per person, cases had higher levels of Glo-3A antibodies than controls at all ages from birth to TTG seroconversion (β = 0.53, P = 0.002). Conclusions: Compared with controls, CD cases have higher Glo-3A antibody responses in the beginning years, before initial detection of TTG.

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. Josephs 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.

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.