Tag Archives: potential celiac disease

Micro-Computed Tomographic Imaging Shows the Blurry Line Between Potential Celiac Disease and Celiac Disease

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A Reunamo et al. Gastroenterology, 2026; 171, 553-555. Open Access! Three-Dimensional Micro-Computed Tomographic Imaging Reveals Early Mucosal Remodeling in Individuals With Potential Celiac Disease

Background: “A subset of individuals, characterized as having potential CeD (PCeD), present with positive transglutaminase 2 or endomysial antibodies, or both, but lack histologic findings that meet the diagnostic criteria.1 Importantly, only a subgroup of individuals with PCeD progress to CeD during follow-up.1“

Methods: The authors “recently developed a 3-dimensional (3D) x-ray micro-computed tomographic (micro-CT) imaging and analysis procedure for duodenal biopsy specimens.6,7 The method enables the precise histomorphometric quantification, including measurements of villus height–to–crypt depth ratio (VH:CrD) and mucosal surface area, with excellent reproducibility.7” This study used micro-CT imaging to investigate the early-stage mucosal changes in individuals initially diagnosed with PCeD. This study enrolled 20 patients with PCeD who progressed to CeD, 5 patients who continued with PCeD, and 16 control individuals.

Key findings:

  • Micro-CT imaging revealed a significantly reduced VH:CrD at both the PCeD and CeD stages compared with the controls, but the difference between PCeD and CeD did not reach significance
  • Only 7/20 with PCeD had normal biopsy VH:CrD values >2.0 across all sites
A) VH:CrD (left) and relative mucosal surface area (right) across PCeD (orange), CeD (blue), and nonCeD control (non-CeD) groups. Box and whisker plot: The boxes indicate the 25th percentile (bottom border), median (center line), and 75th percentile (top border), the whiskers show the maximum and minimum ranges, and the circles indicate outliers

Discussion:

“Most of the PCeD cases were already below the commonly used VH:CrD cutoff when assessed using micro-CT cross-sections, implying that histologic thresholds may lack sufficient sensitivity to capture signs of early CeD.”

My take (borrowed in part from the authors): This study strengthens the “concept that enteropathy in CeD represents a progressive continuum.5 In fact, pinpointing the exact moment when the condition becomes “CeD” is difficult, especially because what is considered normal can vary individually and depending on the biopsy site.” This study may help explain why many symptomatic patients with PCeD respond to a gluten-free diet.

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Celiac Disease: Pro Tips (Part 1)

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In June 2024 (special issue), Gastroenterology published an entire issue (193 pages) focused on celiac disease. There was a lot of useful information on almost every aspect of this disease. Below I have summarized some of the points.

F Zingone et al. Open Access: Celiac Disease–Related Conditions: Who to Test?

  • The authors detail disorders with increased risk for CeD and which merit screening (see Table 2 below). Some disorders that merit screening that are more obscure include idiopathic pancreatitis, autoimmune hepatitis, delayed menarche, and chronic fatigue.
  • They note that type 1 diabetes mellitus could require serial screening. “Because CeD can manifest at any time and with greater frequency during the initial 5 years, conducting additional screenings in CeD-negative T1DM patients 2 and 5 years after T1DM diagnosis and those who later develop gastrointestinal (GI) symptoms may be advisable.” In addition, it is important to recognize that CeD serology testing is less reliable in patients with T1DM.

S Gatti et al. Patient and Community Health Global Burden in a World With More Celiac Disease, describes the worldwide burden of celiac disease and how to improve detection.

  • They note that the worldwide prevalence is between 0.7% and 2.9%. In this issue, most authors estimate the prevalence to be about 1% with more than 50% undetected.
  • There are many places with higher rates. In U.S. “children in Colorado had a 2.5-fold higher risk compared to Washington State…similar regional differences were seen …in Sweden, Finland, and Germany.”
  • They note the burden before and after diagnosis. Before diagnosis/undetected, there can be persistent symptoms, complications (eg. osteoporosis, decreased fertility) and impaired quality of life. Afterwards, there are increased costs of a GFD and psycho-social burden of GFD.
  • In terms of generalized screening compared to case-finding, the authors note that given the number of at-risk groups, the case-finding approach could entail screening >50% of the population.

V Abadie et al. New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease, reviews the intricate details of genetic, biochemical, and immunologic studies, which together have revealed mechanisms of gluten peptide modification and HLA binding, thereby enabling a maladapted anti-gluten immune response.

  • What I was most interested in was the mechanisms behind ‘potential’ celiac disease (PCeD) in which patients have autoimmunity (+serology) but normal histology. In potential CeD, the anti-CD4+ T-cell response is present but decoupled from tissue cytotoxicity. However, notably, IL-21, a cytokine produced by gluten-specific CD4+ T cells in active CeD, is not up-regulated in potential CeD…In addition, patients with potential CeD lack the presence of an epithelial stress response associated with IL-15, HSP70, and HSP27 upregulation in epithelial cells.” “The presence of epithelial stress is a crucial prerequisite for the development of tissue damage.”

“When is Celiac Disease Celiac Disease?”

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A recent study (R Auricchio et al. Gastroenterol 2019; 157: 413-20, and editorial PR Green S Guandalini, pg 293-4) provides insight into the topic of “potential celiac disease.”

It is difficult trying to explain the concept of potential celiac disease (CD) to families.  Potential CD refers to the situation of having positive celiac serology but normal duodenal mucosa. In this study, the authors prospectively followed 280 children (age 2-18 yrs) with 2 consecutive abnormal serological tests (anit-TG2, EMA) along with normal duodenal architecture who continued a diet containing gluten.

Key findings:

  • 42 (15%) developed villous atrophy at median followup of 60 months
  • 89 (32%) became serologically-negative for CD
  • Cumulative incidence of progression to villous atrophy was 43% at 12 years.
  • The strongest predictive factor for villous atrophy was age: 7% of children less than 3 years developed flat mucosa, compared with 51% for age 3-10 and 55% for those older than 10 years

Advice on potential CD from editorial –titled “When is Celiac Disease Celiac Disease?”

  • Review the biopsies: were there adequate biopsy specimens? ≥4 from descending duodenum and ≥1 from duodenal bulb
  • Have a second specialist pathologist review specimens
  • If a patient with potential CD is symptomatic, institute a gluten-free diet and then follow for clinical and serologic response
  • If asymptomatic, “a wait and see approach is appropriate with interval biopsies every 2 years, if the elevated antibodies persist”

The editorial also note that none of the patients in this cohort would have been mislabeled with a diagnosis of CD using the non-biopsy approach as none of them had tTG antibodies >10 times the upper level of normal.

My take: This useful study should help with counseling parents about the likelihood of developing celiac disease in those with the “potential” label.  Younger children (<3 yrs), compared to older children, are less likely to convert from potential celiac disease to actual celiac disease..

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Crater Lake, OR

Reliability of High Serology in Asymptomatic Celiac Disease

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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 study: R 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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Will Asymptomatic Patients with “Potential” Celiac Disease Benefit from a Gluten-free Diet?

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A recent study (Volta et al. Clin Gastroenterol Hepatol 2016; 14: 686-93) indicates that those with “potential” celiac disease, who are asymptomatic, are unlikely to benefit from a gluten-free diet.  A useful summary is available on the AGA blog: What Happens to Patients with Markers of Celiac Disease but No Symptoms?

An excerpt:

Celiac disease is an immune-mediated gluten-dependent systemic disorder characterized by serologic and genetic factors and villous atrophy in the small intestine. Although some people test positive for antibodies and carry genetic alleles associated with celiac disease, they have relatively normal or slightly inflamed intestinal mucosa, with no or mild enteropathy. These patients are considered to have potential celiac disease (defined as increased serum levels of antibodies against tissue transglutaminase [tTG] without villous atrophy). They can have gastrointestinal and extra-intestinal symptoms or be completely asymptomatic…

To learn more about progression of potential celiac disease, Umberto Volta et al performed a prospective study to track clinical, serologic, and histologic features of 77 patients. The subjects had normal or slight inflammation of the small intestinal mucosa and were followed for 3 years.

Sixty-one patients had intestinal and extra-intestinal symptoms and 16 were completely asymptomatic at diagnosis…

Gluten withdrawal led to significant clinical improvement in all 61 symptomatic patients.

Of the 16 asymptomatic patients, who were left on the gluten-containing diets, only 1 developed mucosal flattening; levels of anti-endomysial and tTG antibodies fluctuated in 5 of these patients or became undetectable.

My take: In symptomatic patients (but not asymptomatic patients) with potential Celiac disease, a gluten-free diet may be worthwhile.

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Mina Falls, El Junque

Mina Falls, El Junque

“Gluten-Related Disorders” (Part 1)

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On the way back from our National Meeting (NASPGHAN), I had the opportunity to read “Gluten-Related Disorders” ed. by Alessio Fasano.  The book is a very good summary about the science of celiac disease (CD), wheat allergy, and nonceliac gluten sensitivity (NCGS); at the same time, there is some redundancy due to multiple authors (particularly evident in later chapters). One of the book’s features is clinical vignettes to drive home multiple teaching points.  For example, the ‘refractory’ CD patient who in fact has Crohn’s disease. The book also provides a code to obtain the information online, so it is fully searchable.  In the introduction, there is an in-depth explanation of why gluten can be so difficult for the GI tract.  The discovery that a gluten-free diet can be helpful was a byproduct of wheat shortages during WWII.  Here are some useful insights that were noteworthy:

Definitions (page 9):  reviews the terms “silent CD,” “potential CD,” and “latent CD.”

  • Silent =asymptomatic but with all other features: +antibodies, +HLA type, +abnl histology
  • Potential =+antibodies but lack of histology evidence  (antibodies often precede development of clinical disease)
  • Latent =previous evidence of CD but currently tolerating gluten in diet with normal histology

Epidemiology:

  • While increase in CD is partly due to awareness, there has been a “true increase in prevalence, with rates doubling every 20 years or so.”
  • Early vaccinations are not risk factors for the development of CD
  • Breastfeeding can reduce risk of CD by about 50% though gluten should be introduced between 4-6 months.

Presentation:

  • Table of the main extraintestinal manifestations on page 24.  Most common: anemia (especially iron deficiency), short stature, and pubertal delay.
  • Associated diseases (Table 3, page 29): Down syndrome, Turner syndrome, Type I Diabetes, Williams syndrome, IgA deficiency, and Autoimmune thyroid disease.
  • Eosinophilic esophagitis has been identified in a small number of patients with celiac disease.  The book notes a study with 7 pediatric patients; only one of them improved their esophageal eosinophilia with a GFD.

Tips on diagnosing celiac

  • Bulb abnormalities with a normal 2nd portion of duodenum biopsy can be seen in 10% or more of patients with celiac.  The authors recommend obtaining 4 biopsies from 2nd and 3rd portion and 2 biopsies from bulb (separate containers) (page 144-145).
  • Most celiac experts say there is no celiac without DQ2 or DQ8.  There are several situations in which a negative HLA type could be helpful (page 78)
  1. -negative serology but abnormal histology
  2. -gluten-free diet (GFD) started before diagnosis confirmed
  3. -failure to respond to GFD
  4. -asymptomatic high-risk individuals to help determine if periodic serology is worthwhile
  • In most individuals, obtaining TTG IgA along with serum IgA is recommended for diagnosis (and avoiding older gliadin antibody tests).  If clinical suspicion is high, endoscopy is warranted regardless of result.
  • Under the age of 2, deamidated anti-gliadin antibodies appear months earlier than the TTG in prospective studies, so order the dAGA IgG and dAGA IgA in kids under 2. (Available with both quest and labcorp).  The deamindated anti-gliadin antibodies may be more helpful/sensitive in monitoring dietary adherence than TTG.
  • Infants who have a first degree family member with celiac should be introduced to “small” amounts of gluten between 4 and 6 mos of age – not before and not delayed.  It appears to promote tolerance though it’s not clear if it just delays inevitable onset.  Small amounts can be a serving a day of a mixed, barley baby cereal.
  • Section V is devoted to diagnosis.  Table 1 (page 72) lists the sensitivity/specificity of the available serologies.
  • Screening asymptomatic persons.  The controversy regarding this practice is alluded to on page 75.  Currently NASPGHAN recommends screening at risk groups whereas AGA does not.
  • Endoscopy/Biopsy discussed (pages 78-82).  States a biopsy is not needed in the case of dermatitis herpetiformis due to characteristic deposits of IgA in the dermal papilla.  The authors recommend biopsy in all cases, but review ESPGHAN guidelines which state that biopsy can be omitted if TTG IgA >10 time ULN –if verified by positive EMA, HLA typing, and followed for symptomatic improvement.
  • Antibody tests “become negative in 15% after 1 month on GFD and in 57% after 3 months…diagnosis of CD cannot be made while on GFD.”  Algorithm for diagnosis of CD with a child on GFD presented on page 148.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.