Persistently Abnormal Celiac Labs =High Likelihood of Celiac Disease

CM Trovato et al JPGN 2021; 72: 712-717. Diagnostic Value of Persistently Low Positive TGA-IgA Titers in Symptomatic Children With Suspected Celiac Disease

This retrospective study provides insight into the predictive value of persistently abnormal celiac labs in symptomatic children.

Inclusion criteria:  not eligible for a non-biopsy diagnosis AND children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies

Methods: Patients were classified in groups according to median TGA-IgA values: Group A (TGA-IgA>1 ≤ 5 × ULN; defined as “low-positive”), Group B (TGA-IgA > 5 < 10 × ULN; “moderate-positive”), and C (controls).

Key findings:

  • In group A, CD was diagnosed in 142/162 (87.7%)
  •  In group B, all 62 children (100%) received a CD diagnosis

My take: In individuals with mild elevation of celiac serology, it is reasonable to recheck prior to confirming with endoscopy. However, those with persistently abnormal values are very likely to have celiac disease.

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  • If TTG IgA at 1-fold ULN, then PPV 61%, NPV 98%, Sens 90%, Spec 90%
  • If TTG IgA at 2-fold ULN, then PPV 79%, NPV 97%, Sens 82%, Spec 96%
  • If TTG IgA at 5-fold ULN, then PPV 93%, NPV 94%, Sens 62%, Spec 99%
  • If TTG IgA at 7-fold ULN, then PPV 96%, NPV 91%, Sens 41%, Spec 100%
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Is it Helpful to Check Celiac Serology Titers After 3 Months of a Gluten Free Diet?

A recent prospective study (D Petroff et al. Clin Gastroenterol Hepatol 2018; 16: 1442-49) with 345 pediatric patients with biopsy-proven celiac disease (CD) examined serologic response to a gluten-free diet (GFD) between 2012-2015.

Key findings:

  • Mean TTG IgA concentration decreased 14-fold after 3 months of a GFD.  The study assay used kits from EUROIMMUN.
  • TTG IgA remained above 1-fold ULN in 83.8% and above 10-fold ULN in 26.6%.
  • Deamidated gliadin IgA (DGL IgA) decreased in the vast majority but did not distinguish response of GFD from random fluctuations.
  • The authors note that symptoms improved in most on GFD, but short-term response could reflect “regression to the mean…for a considerable share” as symptoms improved in the non-GFD group as well.

In their discussion, the authors reference a large study (n=487) which showed mean normalization of TTG IgA of ~400 days; longer times were noted in those with type 1 diabetes and higher baseline values.

My take: This study, while showing that TTG IgA levels improve after 3 months of a GFD, helps solidify my opinion that in those who are improving, followup serology could be obtained later.  My practice is to have followup serology after 6 months of a GFD in the majority of patients.

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Reliability of High Serology in Asymptomatic Celiac Disease

Another study (SP Paul et al. JPGN 2018; 66: 641-44) has shown that high anti-TTG IgA levels are reliable in establishing the diagnosis of celiac disease in asymptomatic children from high-risk groups. In this study with prospectively-collected data from 2007-2017, 84 of 157 children had anti-TTG titers >10x ULN.  75 of these 84 were from high-risk groups, mainly type 1 diabetes (36), and first degree relatives (24)

Key finding:

  • All 75 with high titers from high-risk groups had histologic evidence of celiac disease.

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Related studyR Mandile et al. JPGN 2018; 66: 654-56. This prospective study showed that 19 of 35 (54%) patients with potential celiac disease had a complete clinical response on a gluten-free diet to symptoms like abdominal pain and diarrhea.  Thus, in many patients with potential celiac disease, a gluten-free diet will not be effective.

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The Non-Biopsy Diagnosis of Pediatric Celiac Disease

In some corners, experts have suggested the need for a followup intestinal biopsy to assure that celiac disease is responding to a gluten-free diet (Related blog post: Are followup biopsies necessary in celiac disease? Look beyond the headlines).  Meanwhile, many are looking at performing zero biopsies –at diagnosis or later. A recent study (J Wolf et al. Gastroenterol 2017; 153: 410-9) involved a prospective enrollment of 898 children undergoing duodenal biopsy to confirm or rule out celiac disease (CD).  Patients had tissue transglutaminase IgA (TTG IgA), total IgA and deamidated gliadin IgG (DGL-IgG) measured.

Key findings:

  • 592 had CD and 345 did not have CD.  24 did not have a final diagnosis.
  • In examining non-IgA deficient patients that had either TTG IgA >10 times ULN or normal (<1 times ULN), the positive predictive value for CD was 0.988 and the negative predictive value was 0.934.
  • In examining patients with both TTG IgA elevation (>10 times ULN) and DGP-IgG (>10 times ULN) or normal labs, the positive predictive value (PPV) for CD was also 0.988 and the negative predictive value (NPV) was 0.958.  The authors estimated that the PPV and NPV would remain >0.95 even at disease prevalence rates as low as 4%.
  • In this high prevalence population, the authors note that only 23% would have required an endoscopy to confirm or exclude CD; however, they note that in another study using consecutive serologic data, a much higher proportion (57%) needed biopsies due to serology that was <10 times ULN.
  • The authors note that HLA status genotyping, which has been recommended as needed in non-biopsy diagnosis, is not helpful.  Compatible HLA status was noted in all 277 cases of TTG-IgA >10 times ULN and was deemed “unnecessary” by the study authors in those with high titers.

The ESPGHAN guidelines for non-biopsy diagnosis indicate that a repeat serologic study should be performed to exclude a sample mix-up and to only forego biopsies in symptomatic patients.

My take: This study show\ed that individuals with high celiac serology titers have celiac disease >98% of the time.  This information should be discussed with families in determining whether endoscopic biopsy is needed.  Among those who pursue a non-biopsy approach, some individuals could have competing etiologies for their symptoms; thus, a low threshold for evaluation is needed in those who do not respond to a gluten free diet

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

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How Slow Do Objective Markers of Celiac Change After Treatment?

In a recent study (D Gidrewicz et al. JPGN 2017; 64: 362-7) with 228 consecutive, newly diagnosed children with biopsy-proven celiac disease, the authors followed improvement in serology.  Patients were divided into tertiles based on the degree of TTG IgA/EMA abnormalities. For example, Group A had the most abnormal serology: TTG >10 times ULN and EMA ≥1:80.

My take: This data confirms the fact that it takes a long time for resolution of celiac serology, particularly in those with the most severe disease.

Are Followup Biopsies Necessary for Celiac Disease? Look Beyond the Headline

A retrospective study from Boston has gained attention for suggesting that repeat biopsies may be needed for celiac disease (published online, MM Leonard et al JPGN, doi: 10.1097/MPG.0000000000001460).  In my view, this may be a little early for that recommendation for asymptomatic patients with normal serology.

Full Abstract:

Value of IgA tTG in Predicting Mucosal Recovery in Children with Celiac Disease on a Gluten Free Diet.

Objective: Our objective was to determine the rate of mucosal recovery in pediatric patients with celiac disease on a gluten free diet. We also sought to determine whether IgA tissue transglutaminase (tTG) correlates with mucosal damage at the time of a repeat endoscopy with duodenal biopsy in these patients.

Methods: We performed a retrospective chart review of one-hundred and three pediatric patients, under 21 years of age, with a diagnosis of celiac disease defined as Marsh 3 histology, and who underwent a repeat endoscopy with duodenal biopsy at least twelve months after initiating a gluten free diet.

Results: We found that 19% of pediatric patients treated with a gluten free diet had persistent enteropathy. At the time of the repeat biopsy, tTG was elevated in 43% of cases with persistent enteropathy and 32% of cases in which there was mucosal recovery. Overall the positive predictive value of the autoantibody tissue transglutaminase was 25% and the negative predictive value was 83% in patients on a gluten free diet for a median of 2.4 years.

Conclusions: Nearly one in five children with celiac disease in our population had persistent enteropathy despite maintaining a gluten free diet and IgA tTG was not an accurate marker of mucosal recovery. Neither the presence of symptoms nor positive serology were predictive of a patient’s histology at the time of repeat biopsy. These findings suggest a revisitation of monitoring and management criteria of celiac disease in childhood.

Link to full text: A few other key points:

  • The most common indications for repeat endoscopy were due to persistent symptoms (43%) and new gastrointestinal symptoms (27%). Twenty-four subjects (34%) had persistently elevated serology at the time of the repeat biopsy.
  • 19% exhibited persistent enteropathy consistent with a Marsh 3 lesion at the time of the repeat endoscopy.
  • Only 71 patients had serology within 4 months of repeat endoscopy, limiting the interpretation of the concordance of tTG value to histology

My take: I think it is premature to recommend routine followup biopsies in asymptomatic patients with normal serology.  I think a prospective study will be helpful; the majority of patients in this study who underwent repeat biopsy were symptomatic and 9% were not adherent to their diet.  Thus, this may not reflect a typical patient with celiac disease at followup.  In addition, it would be helpful with regard to whether persistent histological findings have clinical significance.

Despite these limitations –this is how this article is being reported (from, here’s an excerpt from a recent summary:

Study finds 1 in 5 pediatric celiac disease patients on gluten-free diet sustain persistent intestinal damage

Alessio Fasano, MD, director of the MGHfC center and co-senior author of the study, was also surprised by the results, which were based on a retrospective examination of the biopsy and medical records of 103 children with celiac disease treated at MGHfC or BCH. The children had been on the gluten-free diet for at least one year and were determined by dietitians and other hospital health care practitioners to have complied well with the diet. But repeat biopsies found persistent intestinal damage in 19 percent of them. “The number of children who don’t heal on the gluten-free diet was much higher than what I expected,” Fasano says.


False-positive Tissue Transglutaminase Antibodies

While tissue transglutaminase IgA antibody is thought to have high specificity for celiac disease, other etiologies need to be considered. As an example, KR Schwartz et al. (NEJM 2016; 374: 1466-76) present a case report which describes a 12 year old who was diagnosed with lymphoma after presenting with anemia, abdominal pain, and fevers. One interesting point was the elevated tissue transglutaminase IgA antibody of 74 (0-15) at presentation; endomysial antibody was negative. The TTG IgA normalized with treatment. The authors note that the presence of TTG IgA antibodies “is not specific for celiac disease but rather is a general phenomenon related to mucosal lesions.”

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