Fluctuating transglutaminase autoantibodies are related to histologic features of celiac disease

doi:10.1053/S1542-3565(03)00180-0

Clinical Gastroenterology and Hepatology

Volume 1, Issue 5, September 2003, Pages 356-362

https://doi.org/10.1053/S1542-3565(03)00180-0 Get rights and content

Abstract

$Background & Aims$ : Asymptomatic children at risk for celiac disease (CD) and seropositive for immunoglobulin A anti-TG autoantibodies (TGAA) may lack small intestinal mucosal changes characteristic of CD. We have followed a group of children with serial testing for TGAA. $Methods$ : Subjects were a group of at-risk children comprised of infants expressing HLA-DR3 on newborn screening, those with type 1A diabetes, or a first-degree relative of someone with type 1 diabetes. All children participating in the prospective study for development of CD underwent serial testing for TGAA. Data from clinical evaluation and small intestinal biopsy were compared to the TGAA levels followed over time. $Results$ : In 42 children, serial TGAA determinations while on a gluten-containing diet showed levels fluctuating 10–100-fold over 3–12 months. A TGAA index more than 0.5 had a positive predictive value (PPV) for histologic confirmation of CD of 96% (22/23). A TGAA index above the usual cutoff for positivity (0.05) had a PPV of only 76% (28/37). $Conclusions$ : In children with TGAA seropositivity, the TGAA level varied over time and a higher titer predicted an abnormal biopsy characteristic of CD. A threshold for biopsy for diagnosis of CD could be set higher for screening-identified cases than for clinically identified cases to decrease the frequency of performing “normal” biopsies.

Section snippets

Patient population

Children with 2 types of genetic risk for CD were recruited into this study between 1995 and 2001 (Figure 1). In the first group, newborns with HLA-DR3 were enrolled in the study. To date, more than 25,000 newborns have undergone cord blood HLA genotyping. From this group, 1083 have been selected for prospective monitoring for the development of TGAA as described previously.17 In the second group, children with type 1A diabetes in themselves or a first-degree relative were enrolled. Eighty-six

Results

Persistent TGAA seropositivity was identified in 52 children: 25 of 1083 (2.3%) in the newborn group with DR3, 5 of 86 (5.8%) in subjects with type 1 diabetes, and 22 of 773 (2.8%) in first-degree relatives of patients with diabetes (Figure 1). Of 42 who underwent small intestinal biopsy, 28 of 42 (67%) had evidence of CD (Marsh score 2 or 3), and 12 of 42 (29%) had normal biopsy specimens (Marsh score of 0). Two subjects had indeterminate biopsy specimens (Marsh 1). Once present, TGAA remained

Discussion

We have shown that some children with a genetic risk for CD demonstrate fluctuating TGAA levels. The TGAA levels obtained at the time of biopsy correlate with the degree of small intestinal injury. Our findings provide evidence of a dynamic process of autoimmunity characterized by intestinal injury and healing. Whether TGAA has a causal relationship to the intestinal injury is unclear.

Our findings have several important clinical implications. First, the model of a dynamic autoimmune process

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Raising the Cut-Off Level of Anti-Tissue Transglutaminase Antibodies to Detect Celiac Disease Reduces the Number of Small Bowel Biopsies in Children with Type 1 Diabetes: A Retrospective Study
2020, Journal of Pediatrics
Citation Excerpt :
In our cohort, 55% of the children with Marsh 0 or 1 histology were also symptomatic, which may reflect the fact that the symptoms are nonspecific for CD. Our results are in line with those of several recent studies in children with T1DM showing that TG2A levels varying from 5 to 8 to 10 times the ULN were stronger predictors of villous atrophy than values of more than three times the ULN.7,8,15,16 Although screening tests usually optimize sensitivity to find new patients, specificity is the measure that needs optimization to avoid false-positive results.17
To study the optimal cut-off value for anti-tissue transglutaminase type 2 IgA antibodies (TG2A) in serum to select for diagnostic small bowel biopsies for celiac disease in children with type 1 diabetes mellitus.
Children with type 1 diabetes mellitus with elevated TG2A titers and duodenal biopsies performed during the course of their diabetes treatment were included. Anti-endomysial antibodies were recorded if present. The optimal TG2A cut-off value, expressed as the ratio between obtained value and upper limit of normal (ULN), was determined using receiver operating characteristic curve analysis and compared with the cut-off value used in the European Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines in terms of sensitivity, specificity, positive and negative predictive value.
We included 63 children. The optimal cut-off value for performing biopsies is demonstrated to be 11 times the ULN. Raising the cut-off value from 3 times the ULN to 11 times the ULN changed sensitivity from 96% to 87% and increased specificity from 36% to 73%, increased the positive predictive value from 88% to 94% and lowered negative predictive value from 67% to 53%. The percentage of normal histology was decreased from 12% to 6%.
Increasing the TG2A cut-off value for performing duodenal biopsies in children with type 1 diabetes mellitus and suspected celiac disease leads to a substantial reduction of unnecessary biopsies. We advocate to adapt the European Society for Pediatric Gastroenterology, Hepatology and Nutrition 2012 guidelines for this group of children, including monitoring patients with TG2A levels of less than 11 times the ULN over time.
Community-Based Study of Celiac Disease Autoimmunity Progression in Adults
2020, Gastroenterology
Citation Excerpt :
van Koppen et al31 conducted a 10-year follow-up study of children with CeD and found that 1 of 6 asymptomatic children with seropositive results for CeD had spontaneous seroconversion (going from positive to negative). Another group who studied pediatric CeD found transient or fluctuating CeD serologic results: of the 46 patients who had positive serologic results for CeD at one point, 46% had a subsequent loss of tTGA at follow-up testing, and 13% had even fluctuations of tTGA levels, oscillating between positive and negative levels in multiple follow-up testings.2,11 In another study, Castellaneta et al13 also found that serum tTGA levels became negative in 20% of children with type 1 diabetes mellitus despite gluten consumption.
Celiac disease can develop at any age, but outcomes of adults with positive results from serologic tests for tissue transglutaminase antibodies (tTGA) without endoscopic determination of celiac disease (called celiac autoimmunity) have not been thoroughly evaluated. We investigated the proportion of adults with celiac autoimmunity at a community medical center and their progression to celiac disease.
We analyzed waste blood samples from a community clinic from 15,551 adults for tTGA and, if titer results were above 2 U/mL, for endomysial antibody. The blood samples had been collected at 2 time points (median interval, 8.8 years) from 2006 through 2017. We collected data from the clinic on diagnoses of celiac disease based on duodenal biopsy analysis.
Of the serum samples collected at the first time point, 15,398 had negative results for tTGA, and 153 had positive results for tTGA (>4 U/mL). Based on medical records, 6 individuals received a diagnosis of celiac disease, for a cumulative incidence of celiac disease diagnosis of 0.06% (95% confidence interval, 0.01–0.11). Forty-nine (0.32%) individuals with a negative result from the first serologic test for tTGA had a positive result from the second test. Among the 153 adults who were tTGA positive at the first time point, 31 (20%) had a subsequent diagnosis of celiac disease, 81 (53%) remained positive for tTGA without a clinical diagnosis of celiac disease, and 41 (27%) had negative test results for tTGA at the second time point. Higher initial tTGA titers, female sex, and a history of hypothyroidism and autoimmune disease were associated with increased risks of subsequent diagnosis of celiac disease. Interestingly, adults whose first blood sample had a positive test result but second blood sample had a negative result for tTGA were older, had lower-than-average initial tTGA titer results, and had a higher mean body mass index than adults whose blood samples were positive for tTGA at both time points and adults later diagnosed with celiac disease.
In an analysis of serum samples collected from a community clinic an average of 8.8 years apart, we found that fewer than 1% of adults with negative results from an initial test for tTGA have a positive result on a second test. Of adults with positive results from the test for tTGA, only 20% are later diagnosed with celiac disease; the remaining individuals maintain persistent increases in tTGA without diagnoses of celiac disease or have negative results from second tests.
High Incidence of Celiac Disease in a Long-term Study of Adolescents With Susceptibility Genotypes
2017, Gastroenterology
Citation Excerpt :
Such transient autoantibodies may limit public acceptance of universal screening.32 Others also have observed fluctuating tTGA15 and transient tTGA antibodies in children with serial testing.33–35 Continued long-term follow-up evaluation will identify whether the autoimmunity in these subjects truly abates and tolerance develops, or if CDA will recur in time, possibly in response to additional stimulating events.
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.
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.
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.
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.
Prediction of Autoimmune Disease
2013, The Autoimmune Diseases: Fifth Edition
Autoimmune diseases are chronic in nature with a long asymptomatic preclinical period. The development of specific markers of the autoimmune process including autoantibodies and T cells assays has led to the ability to identify individuals at high risk for the development of autoimmune disease. Identification of such individuals may allow for the prevention of disease. Type 1 diabetes has been extensively studied and serves as a model for the development of organ-specific autoimmune diseases. It is proposed that subjects go through a predictable pathway beginning with genetic susceptibility, progressing through evidence for autoimmunity, and evidence for metabolic dysfunction including abnormal first phase insulin response and impaired glucose tolerance, eventually culminating in clinical symptoms leading to the diagnosis of type 1 diabetes. Similar models can be developed for other autoimmune diseases including Addison’s disease and autoimmune thyroid disease.
Prevalence and natural history of potential celiac disease in at-family-risk infants prospectively investigated from birth
2012, Journal of Pediatrics
To evaluate the frequency and the natural history of potential (serology positive/Marsh 0-1 histology) celiac disease (CD) in children with a family risk of CD and factors associated with potential instead of overt (serology positive/Marsh 2-3 histology) CD expression.
Two-year follow-up study of 96 children (57 females; mean age: 29 ± 12 months) prospectively investigated from birth with: (1) a CD-affected first-degree relative; (2) positivity of serum IgA anti-tissue transglutaminase (tTG) or IgG antigliadin and IgA deficiency; and (3) the results of small intestinal biopsy. Children with potential CD were advised to remain on a gluten containing diet, repeat the celiac antibodies every 6 months, and to have an intestinal biopsy performed in case of persistently high anti-tTG level. Factors discriminating between potential and overt CD were analyzed by decision tree analysis based on the C4.5 algorithm.
Twenty-four children had potential and 72 overt CD. The stronger predictors of potential CD were lack of symptoms, anti-tTG level lower than 11-fold the upper normal limit, age lower than 24 months, and breastfeeding longer than 8 months. Eighteen out of 21 (86%) patients with potential CD continuing a gluten-containing diet became antibody negative, 1/21 (5%) developed overt CD, and 2/21 (9%) had fluctuating antibodies levels after 2 years.
The prevalence of potential CD and the percentage of short-term loss of CD-related-antibodies are high in infants at-family-risk for CD. In symptomless children with a positive celiac serology, the decision of performing an intestinal biopsy should be preceded by a period of repeated serological testing.
High tissue-transglutaminase antibody level predicts small intestinal villous atrophy in adult patients at high risk of celiac disease
2012, Digestive and Liver Disease
Duodenal biopsy may be unnecessary to confirm celiac disease in patients with high tissue-transglutaminase antibody level.
To define a cut-off value of tissue-transglutaminase antibody with high positive likelihood ratio for duodenal atrophy in patients with suspected celiac disease.
We retrospectively identified 945 patients with suspected celiac disease and classified according to the method used for tissue-transglutaminase antibody assay: Group A (n = 393, Eu-tTG^® Eurospital), Group B (n = 263; Eu-tTG^® Eurospital) and Group C (n = 289; Celikey^® Phadia). Duodenal histology was graded according to Marsh. Sensitivity, specificity, and positive likelihood ratio were used to evaluate cut-off points of tissue-transglutaminase antibody as predictor of villous atrophy.
100% specificity and ∞ positive likelihood ratio for duodenal atrophy was observed at a cut-off value of tissue-transglutaminase antibody 5 times higher than the upper limit of normal. CD diagnosis was confirmed by concordance with antiendomysial antibodies, and by reduction of t-TG titre in all patients and improvement of duodenal histology in 80% during gluten-free diet.
Tissue-transglutaminase antibody level 5-folds the upper limit of normal is 100% specific for duodenal atrophy and using this cut-off biopsy could by avoided in 1/3 of patients. Diagnostic criteria of celiac disease in adults need revision.

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^☆: Supported by National Institutes of Health grant M01RR00069, General Clinical Research Center program in the National Center for Research Resources, NIH grants DK RO1-DK50979, DK32083, DK32493, Autoimmunity Center of Excellence grant U19AI46374, Diabetes Endocrine Research Center P3057516, Autoimmunity Prevention Center grant 5U19AI50864, and Immune Tolerance Network Autoantibody Core Laboratory. Dr. Liu is supported by the NIH training grant T32 AI07365.

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Original articleFluctuating transglutaminase autoantibodies are related to histologic features of celiac disease☆

Abstract

Section snippets

Patient population

Results

Discussion

Gastroenterology

Hum Immunol

Lancet

Hum Immunol

Hum Immunol

J Autoimmun

J Pediatr

J Pediatr

Gastroenterology

J Pediatr

Am J Gastroenterol

Am J Gastroenterol

Celiac sprue

N Engl J Med

Interplay between genetics and the environment in the development of celiac diseaseperspectives for a healthy life

J Clin Invest

Screening for antibodies against gliadin in patients with osteoporosis

J Intern Med

A combination of a particular HLA-DPβ allele and an HLA-DQ heterodimer confers susceptibility to coeliac disease

Nature

Serological markers and HLA-DQ2 haplotype among first-degree relatives of celiac patients. Catalonian Coeliac Disease Study Group

Dig Dis Sci

HLA-DQA1∗0501 and DQB1∗02 homozygosity and disease susceptibility in Spanish coeliac patients

Exp Clin Immunogenet

On the HLA-DQ(α1∗0501, β1∗0201)-associated susceptibility in celiac diseasea possible gene dosage effect of DQB1∗0201

Tissue Antigens

Original article
Fluctuating transglutaminase autoantibodies are related to histologic features of celiac disease☆