Is Autoimmunity Associated with Nonceliac Wheat Sensitivity?

According to a recent study (A Carroccio, et al. Gastroenterol 2015; 149: 596-603), patients with nonceliac wheat sensitivity (NCWS) (aka. nonceliac gluten sensitivity or wheat intolerance syndrome) are more prone to developing autoimmune disorders compared with patients with irritable bowel syndrome.

Given the difficulty identifying NCWS, the findings must be viewed cautiously; in addition, much of this study was a retrospective study.

Background: The authors identified 131 patients diagnosed with NCWS (121 female) with a mean age of 29 years.  They compared these individuals to control groups of patients with either celiac disease (CD) or irritable bowel syndrome (IBS).  In addition to the retrospective study, the authors prospectively examined 42 patients diagnosed with NCWS (2011-2014).  These diagnoses were established by double-blind placebo-controlled wheat challenge.

Key findings:

  • In the retrospective analysis, 29% of NCWS patients and 29% of CD developed autoimmune diseases (mainly Hashimoto’s thyroiditis, 29 cases) compared with a smaller proportion of subjects with IBS (4%) (P<.001).
  • In the retrospective analysis, 46% of NCWS, 24% of CD and 2% of IBS developed ANA antibodies (median titer 1:80).
  • In the prospective arm, 24% of NCWS, 20% of CD, and 2% of IBS subjects developed autoimmune disease.
  • Similarly, in the prospective arm,  28% of NCWS, 7.5% of CD and 6% of U+IBS developed ANA antibodies (median titer 1:80).
  • ANA positivity was associated with the presence of HLA DQ2/DQ8 haplotypes (P<.001).  ANA positivity, to a lesser extent, was associated with the presence of duodenal lymphocytosis (grade A histology).

The authors note that “these associations strongly suggest a celiac condition, but it must be emphasized that all the patients we included were negative for CD-specific antibodies and showed normal intestinal villi” with a gluten challenge.

Potential limitations included a selection bias of patients referred to this tertiary center.

My take: This study suggests significant overlap between CD and NCWS.  The real frequency of autoimmunity in NCWS is unclear as this study population is not likely representative of most patients who go gluten-free.

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“Men Sometimes See Exactly What They Wish To See” and Gluten Sensitivity

For me, a recent study (AD Sabatino et al. Clin Gastroenterol Hepatol 2015; 13: 1604-12, editorial 1613-15) was particularly interesting.  While it had “positive results,” these findings were based almost entirely on the results of three patients.

In brief, this study examined 61 adults (w/o celiac disease) who believed that gluten induced intestinal and extraintestinal symptoms.  These individuals were randomized to receive either 4.375 g/day of gluten or rice starch via capsules.  This amount of gluten is equivalent to 1 sandwich or 2 slices of bread.


  • Overall, intake of gluten significantly increased symptoms compared to placebo (P=.034), including bloating, pain, foggy mind, depression, and aphthous stomatitis.
  • Looking at a scatterplot (Figure 4), it is abundantly clear that all of these findings are driven by 3 patients.
  • “In the vast majority of patients the clinical weight of gluten-dependent symptoms was irrelevant in light of the comparable degree of symptoms experienced with placebo”
  • “Our study did not provide any progress in identifying possible biomarkers of NCGS [non-celiac gluten sensitivity]”

This type of study, with mixed conclusions, led the editorialists to quote Spock (from Star Trek):

“In critical moments, men sometimes see exactly what they wish to see.”

Then, the editorial provides a historical context of NCGS with a review of the relevant prior studies.  Other comments:

  • “These findings can be a Rorschach test of sorts, in which the viewer draws interpretations that are  based on his or her prior beliefs about NCGS.”
  • The authors note that both the gluten and the control arm likely had a significant nocebo effect (negative placebo effect),
  • “This trial, like its predecessors, seems only to contribute to the uncertainty about NCGS.”

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Wheat Intolerance Syndrome?

Even though we’ve lived in our house for many years, some of our neighbors refer to our house as the ‘Walden’ house; the Waldens lived here for a long time before we did. Probably when we move, our neighbors will call our present home the “Hochman” house, regardless of who resides there.

I think nomenclature in medicine has a similar reluctance to adopt new terms.  A recent medical progress report (Guandalini S, Polanco I. J Pediatr 2015; 166: 805-10) suggests dropping the term “Nonceliac gluten sensitivity” (NCGS) in favor of “Wheat Intolerance Syndrome.”

It’s probably a good idea and their arguments are sound. Two key points:

  • “There is no proof that gluten is causing NCGS.”
  • It is likely that the majority of patients considered NCGS have not even eliminated celiac disease before instituting a gluten-free diet.

With regard to the first point, the authors note that recent studies have suggested that a “FODMAP” (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet is likely the culprit in many cases of so-called NCGS.  They review a pivotal double-blind study (see related blog post: An Unexpected Twist for “Gluten Sensitivity” | gutsandgrowth) there was no role for gluten “at least in these patients with IBS-like NCGS.”  In addition, other studies have demonstrated a strong role for a placebo/nocebo effect of dietary elimination.  “It is quite conceivable that a portion of patients with NCGS, and arguably a substantial one, fall in this category.”

With regard to the second point, it is not a good idea to initiate a gluten-free diet before excluding the diagnosis of celiac disease (hence the prior term: “nonceliac” gluten sensitivity).  A related comment from the authors is that a “Grade 1 [Marsh] intestinal lesion has traditionally been considered of a very low specificity for celiac disease.”  More testing in this circumstance can help determine if celiac disease is the reason, including checking the levels of ϒδ T-cell receptors in intraepithelial lymphocytes (very specific for celiac disease) and/or detection of IgA anti-tissue transglutaminase antibody deposits in intestinal mucosa.

Other pointers:

  • Genetic testing for HLA-DQ2 and/or HLA-DQ8 genotypes (which are nearly 100% in celiac disease) are present in about 40% of NCGS which does not differ from the general population
  • “Estimating the prevalence of NCGS is impossible.”  Estimates have ranged from 0.6% of the U.S. population to as high as 50% according to some websites.

Bottomline: While “Wheat Intolerance Syndrome” works fine for me, I think the term nonceliac gluten sensitivity is going to be around for a while.  Hopefully, more families and care providers will exclude celiac disease before contemplating this label and consider other foods as potential contributors to the symptomatology.

Related Reference: “Coeliac Disease and Noncoeliac Gluten Sensitivity” Meijer CR, Shamir R, Mearin ML. JPGN 2015; 60: 429-32.  This reference covers much of the same territory.  The Table 1 in this article nicely summarizes the relevant literature/studies from 2008-2014.

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Use of Gluten-Free Diet with Inflammatory Bowel Diseases

As noted in a previous blog (The Search for a Dietary Culprit in IBD | gutsandgrowth), alternative diets have been explored both for symptom improvement and in efforts to improve inflammation in individuals with inflammatory bowel diseases (IBD).  A new study from North Carolina indicates that nearly 20% of patients have tried a gluten-free diet (GFD) to help control clinical symptoms in IBD (Inflamm Bowel Dis 2014; 20: 1194-97).

While adoption of a GFD clearly is effective for celiac disease, it has become popular, along with a low FODMAPs diet, as an alternative treatment for irritable bowel syndrome (IBS)/and “non-celiac gluten sensitivity.”  Since IBS is a common comorbidity with IBD (see recent blog: New Biomarker for Crohn’s Disease (Plus Two ), it is not surprising that a GFD would be used by some with IBD.  In this study, the authors performed a cross-sectional study using a GFD questionnaire in 1647 IBD patients though a CCFA longitudinal internet-based cohort.


  • 19.1% had previously tried a GFD and 8.2% reported current use of GFD.
  • 65.6% described improvement while on a GFD.  Improved symptoms included fatigue, nausea, bloating, abdominal pain, and diarrhea.
  • 0.6% of patients reported a concurrent diagnosis of celiac disease (which is similar to overall celiac prevalence in U.S.)

Given the structure of this study, which is mainly an internet survey, there are many limitations in its interpretation.  Certainly, this study does not prove that a GFD is effective for IBD.  However, it is clear that a GFD is used frequently and may improve IBD/IBS symptoms.

Take-home message: Particularly in patients who have ongoing symptoms despite  mucosal healing, pursuing either a low FODMAPs diet or a GFD may be helpful.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects), implementation of diets 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.

“Gluten-Related Disorders” (Part 2)

Non-celiac Gluten Sensitivity NCGS -Focused discussion in Section III
  • No biologically measurable response has been found – these are people with normal celiac serology (neg ttg/ema) and normal biopsies.
  • Specific discussions regarding autism and schizophrenia.  On page 44, authors note that a 2008 Cochrane review concluded the evidence for a gluten-free diet for autism was poor.  In 2012, a two-stage RCT (Whiteley et al) of gluten-free casein-free diet reported significant group improvements after 8 and 12 months on diet. Thus, diet may be helpful.
  • Other chapters allude to NCGS as well.  Page 124: “There are no epidemiologic studies assessing the prevalence of NCGS. Bizzaro et al estimated that for every one person with CD, there are at least six to seven with gluten sensitivity.”
Wheat Allergy -Section IV
  • Forms include oral food allergy, “wheat-dependent, exercise-induced anaphylaxis,” and Baker’s asthma (aerosolized exposure).
  • Skin prick tests or RAST’s are notorious for providing a high rate of false-positive results.  Low rate of false negative results, though, are noted.

Treatment -Section VI:

  • This section provides a number of tables to assist with diet and hidden sources of gluten.
  • GFD may lead to specific nutrient deficiencies: fiber, iron, folate, niacin, zinc, vitamins B12, A, D, E, and K; also, GFD may be higher in fat.

Psychological Aspects -Section VII:

 “The family has to buy gluten-free foods and all members have to learn how to avoid contaminating gluten-free foods, dishes, toasters, and so on.” Parents have to read all food labels and prepare special meals while attending social events.
A nice sample letter is included on page 129 –should make a good EPIC smartphrase.
Difficult Cases -Section VIII:
  • Labs to check in sick CD patient (Table 2 -page 133).
  • Causes of Nonresponse to GFD: poor compliance, accidental ingestions, nonceliac disease causing symptoms.
  • While some of the authors state that true refractory disease is “rare in adults,extremely rare in children,” in other parts of the book it is noted that complete histologic response is not seen in all patients (some with apparently good adherence).

IgA deficiency (page 139).

  • 85-90% of IgA deficient patients have no clinical symptoms.  Occurs in about 1 in 300.  For those with symptoms, manifestations could include sinopulmonary disease, allergy/atopy, autoimmune diseases, giardiasis/infections, and transfusion reactions (against IgA) (see Table 8 on page 143).
  • Transiently low IgA is common in children <4 years.
  • For IgA deficient patients, risk of CD is 10-20 times general population.
  • In true deficiency, level is typically <7 mg/dL.  More often, there is a partial deficiency which is ‘almost always asymptomatic.’  In partial IgA deficiency, IgA assays identify about 90% of CD cases.
Also, in the difficult cases section an algorithm for follow-up of newly diagnosed CD is presented and discussed (page 154).  Recommendations include nutritional counseling, resource identification, family screening, and celiac education.  Consider checking iron status, vitamin D, folate, zinc, copper and DEXA.  Recommends followup serology 6 months following diagnosis and if normal, then on a yearly basis.
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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.

“Gluten-Related Disorders” (Part 1)

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


  • 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.


  • 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.