Wheat Intolerance –Self-Reported in 15%!

A recent study (MDE Potter et al. Am J Gastroenterol 2018; 113: 1036-44 -thanks to Ben Gold for this reference) examined the frequency of wheat intolerance and chronic gastrointestinal symptoms in a randomly selected population of 3542 in Autstralia via a mail survey.

Key findings:

  • Self-reported wheat sensitivity was 14.9%
  • Prevalence of celiac disease (CD) was 1.2%
  • A doctor-diagnosis of CD was associated with functional dyspepsia with an odds ratio (OR) of 3.35.
  • Self-reported wheat sensitivity was independently associated with irritable bowel syndrome with an OR of 3.55 and almost half (45%) have an underlying functional GI disorder.

In a related editorial (pgs 945-8), Imran Aziz makes several useful points:

  • Gluten-free industry has boomed in U.S. with retail sales going from $0.9 billion in 2006 to ~S24 billion in 2020.
  • While previous studies have shown that gluten can induce symptoms in the absence of CD (Biesiekierski JR et al. Am J Gastroenterol 2011; 106: 508-14), more recent rigorous studies have indicated that “gluten-per-se accounts for 1-in-6 cases with the remaining majority either due to fructans (a type of FODMAP or a nocebo effect.”
  • There are no accurate biomarkers of wheat intolerance
  • Dr. Aziz also cautions against adopting a gluten-free diet without proper counseling.  “The greatest concern is whether these diets are safe in the long-run, given the emerging data suggesting cardiovascular, nutritional, metabolic, and microbial changes.”

My take: This study shows that about 1 in 10 individuals have self-reported wheat intolerance; gluten, though, is the actual culprit in less than 20%.

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Nutrition Symposium Georgia AAP (Part 2)

Last week I summarized an excellent talk by Ronald Kleinman.  For me, I had never heard such a concise and definitive rebuttal of the claims of those fearful of food biotechnology.  There were three other lectures at the symposium.  These three lectures covered areas that are well-known to pediatric gastroenterologists but less familiar to general pediatricians.  The full set of slides are available at the Georgia AAP Symposium Website.

Jeff Lewis had an excellent lecture that tied together gluten and our microbiome: Gluten – Eat not, suffer not and Microbiome 101: Waste Not, Want Not

After reviewing celiac disease and other wheat-related disorders (eg. wheat intolerance syndrome, and wheat allergy), he summarized a great deal of information regarding the human microbiome and which factors influence this. In addition, he had the opportunity to briefly present data from his research on fecal microbiota transplantation (for C diff) and its influence on the microbiome over time. Here are a couple of slides from his talk:


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Key points:

  • “It is hard to communicate science to families. It is a huge challenge for us.”
  • Dermatitis herpetiformis (rare in kids), a rash associated with celiac disease, can be treated with Dapsone. This rash has caused such severe itching that there are cases of suicide that have been reported.
  • For celiac disease, Dr. Lewis recommends testing of 1st degree relatives but this needs to be after gluten exposure and before gluten-free diet.
  • Wheat allergy reviewed. Skin test positivity does not prove that you are allergic to food. IgG based testing is worthless –it means you have been exposed to a food, but is not an indication of food allergy.
  • Nonceliac gluten sensitivity (aka. wheat intolerance syndrome): need to test for celiac first. No tests/biomarker that can confirm this diagnostic. This appears to be a true disease; there is a small subset of patients who develop symptoms with a double-blind challenge.
  • Microbiome –more bacterial DNA in us than human DNA. New organisms –archaea kingdom.  Now a specimen of a person’s microbiome can be run for <$50.
  • Microbiome terms: Richness, Diversity, and Dysbiosis. Many diseases are associated with dysbiosis (obesity, IBD), but there is a ‘chicken and the egg’ problem. Is dysbiosis a causal factor or a secondary factor?
  • Xyloglucans (in lettuce) –not broken down by humans and affected by gut bacteria.
  • Mice given stool from fat mice or fat person become heavy.

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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Atlanta Botanical Gardens

Atlanta Botanical Gardens

“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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Yellowstone Canyon

Yellowstone Canyon


Best Tweets from Postgraduate Course: #NASPGHAN15

Since I am not at this year’s national meeting, I have followed some of the information on social media.  Here are some of the best tweets:

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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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