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A Consensus on Diagnosis of Gluten Sensitivity? Not so Fast.

By: Peter Olins, PhD and Gillian Olins, PhD, on February 10, 2012.

There has been increasing interest in “gluten sensitivity” as a condition that may be distinct from the well-understood conditions of wheat allergy or celiac disease. It has been widely reported that many people feel better after going on a gluten-free diet, and these people often do not fit neatly into the known categories of wheat allergy or celiac disease.

A recent meeting of some of the world’s experts on celiac disease was convened in an attempt to reach some consensus about non-celiac gluten sensitivity, and the outcome has just been published (Ref. 1). The proposals presented by these authors will probably be more of an “opening salvo” than the last word.

 Key conclusions

  • The preliminary recommendation from this group was diagnosis by a process of elimination: once wheat allergy or celiac disease are ruled out, but there are symptoms which appear to be relieved by a gluten-free diet, then the patient is deemed “gluten-sensitive”.
  • The report includes detailed descriptions of wheat allergy and celiac disease, including symptoms, diagnosis, cause and treatment, but unfortunately adds little insight into to the nature of gluten sensitivity.
  • An important new finding was that only a tiny fraction (6%) of patients attending a celiac disease clinic fit the proposed criteria for “gluten sensitivity”, so this may be a rare phenomenon in the general public.
  • In our opinion, since it is not clear whether this is a single condition or multiple associated ones, and since it is not even clear if gluten is the culprit, it may be premature to create this new classification.

How common is non-celiac gluten sensitivity?

The phenomenon of non-celiac gluten sensitivity has attracted increasing interest in the clinical community, but little progress has been made, partly because there have been no agreed-upon criteria that can be used to define the condition, and partly because there is no diagnostic test that is specific for this phenomenon. In the absence of these, it is not clear whether this is a single condition, or a combination of related food intolerances.

There have been widely-circulated estimates of the prevalence of this condition in the popular press, but unfortunately no hard data have been published until now. The current study (Ref. 1) reports that only 6% of 5,896 patients seen at the Center for Celiac Research, University of Maryland met the criteria for gluten sensitivity. Estimates from large CD clinical centers have varied considerably, but it is hard to compare these estimates given the lack of consensus criteria for gluten sensitivity. In addition, patients attending research centers are likely to represent those most sick, rather than a cross-section of the general public. We suspect that some of the popular estimates for the prevalence of gluten sensitivity may be highly exaggerated.

The current report is a useful first step: if the research community can reach agreement on what constitutes “gluten sensitivity”, then it should be possible to devise clinical trials to investigate how common the condition is in the general population.

Ref. 1:  Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine 2012, 10:13 doi:10.1186/1741-7015-10-13 Sapone, A, et al.

What about silent or latent celiac disease, or undiagnosed disease?

One topic that was not discussed in this report was the fact that many people with celiac disease are not readily diagnosed using current techniques, and this process can take years (Ref. 2). In addition, unlike a simple black or white situation (such as a bacterial infection), celiac disease is a spectrum of conditions which may only develop into “full-blown” celiac disease after a number of years. The definition of celiac disease continues to evolve as the mechanism becomes better understood (Ref. 3,4). Typically, celiac disease is definitively diagnosed at a late stage of intestinal damage; however, there must be a progression towards this “classical” state, and many patients have been shown to have mild symptoms or mild intestinal damage (Ref. 5). Are these to be included in an expanded celiac disease diagnosis, or do they fit into non-celiac gluten sensitivity?

Ref. 2:  Improving celiac disease testing

Ref. 3: ESPGHAN guidelines diagnosis coeliac disease children/adolescents. An evidence-based approach http://bit.ly/zDMvrE

Ref. 4:  European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. Husby, S, et al.

Ref. 5:  Latent coeliac disease or coeliac disease beyond villous atrophy? Gut. 2007 October; 56(10): 1339–1340. doi: 10.1136/gut.2006.113084.  Kaukinen, K, et al.

Is gluten even the culprit?

Since a definitive clinical trial has not yet been conducted, it is too soon to conclude that the protein “gluten” is even the culprit. Contrary to popular belief, wheat “gluten” is actually a very complex mixture of different proteins, and the roles of these different components in celiac disease is only starting to be understood (Ref. 6). There is no reason to assume that the peptide segments most important for development of celiac disease are the same as those responsible for gluten sensitivity.

Wheat or gluten?

In an initial study (Ref. 7), a “gluten-challenge” was used to select patients who were “gluten-sensitive”, but it was not mentioned whether purified gluten was used, or simply dietary wheat. This might make a big difference in how doctors would perform a gluten-challenge on their patients. (It should be pointed out that even for celiac disease diagnosis, there is still ambiguity in the amount of dietary wheat to use and the length of challenge required).

Since so little is known about the phenomenon, or whether gluten is even the main player, we think that the term “gluten-sensitivity” may be a little premature. Instead, this is a family of one or more conditions that could more accurately be described as “wheat intolerance of unknown origin”.

As the authors stress, definitive answers can only come with randomized, placebo-controlled clinical trials.

In the mean time, individuals will no doubt do their own subjective sleuthing, to try and figure out which component of their diet is associated with their individual manifestation of “gluten-sensitivity”, even though this is not recommended, since it can interfere with celiac disease diagnosis.

Role of HLA type?

The majority of cases of celiac disease are associated with HLA-DQ2 or DQ8 haplotype. However, gluten sensitivity symptoms can occur even in the absence of the HLA serotypes which are strongly associated with celiac disease (Ref. 7, 8). This indicates that the mechanism of gluten sensitivity may be quite distinct from that of celiac disease or wheat allergy. We note that the authors of the report do not include haplotype as part of criteria for celiac disease diagnosis.

Recent work on the development of animal and cellular models of the different aspects of celiac disease may be helpful in understanding the mechanism of gluten sensitivity (Ref. 9, 10), but clearly the research on the mechanism of gluten sensitivity is still in its infancy.

Ref. 6:  Proposed FDA Standard for Gluten-Free Foods (20 ppm) May Not Adequately Protect the Food Supply for Celiacs http://ultimateglutenfree.com/2011/08/fda-20-ppm-regulation-gluten-free-food-celiac-disease/

Ref. 7:  Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivityBMC Med. 2011; 9: 23 doi:10.1186/1741-7015-9-23 Sapone, A., Lammers, KM., et al.

Ref. 8:  Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry 2002;72:560-563 doi:10.1136/jnnp.72.5.560 Hadjivassiliou, M. et al.

Ref. 9: Important lessons derived from animal models of celiac disease. Int Rev Immunol. 2011 Aug;30(4):197-206. Marietta, EV, et al.

Ref. 10: In vitro models for gluten toxicity: relevance for celiac disease pathogenesis and development of novel treatments. Exp. Medi. Biol. 2012, doi: 10.1258/ebm.2011.011294   Lindfors, K, et al.

Who would benefit from such a new designation of gluten sensitivity?

Who is the audience for this new definition, the researcher or clinician? These two groups have quite distinct needs. Researchers need precise definitions based on well-controlled experiments to test different hypotheses, and often work with large groups of samples or patients. In contrast, clinicians are much more focused on making a decision on how to treat a single individual (even in the face of incomplete knowledge).

A possible downside to a declaration of “gluten sensitivity”?

The vast majority of celiac disease cases are undiagnosed, and a positive diagnosis can take years. We are all aware of examples of patients who have had to battle their physicians over a diagnosis of something that they believed was real, but which was not acknowledged by their physician. CD diagnosis can be tedious, time-consuming and costly. We are concerned that for a given patient the lack of a clear initial CD diagnosis might result in some doctors (and insurance companies?) declaring a simple case of “gluten-sensitivity”, for which no treatment or follow-up is required.

What’s needed

We need more researchers and clinicians to be involved in generating a consensus on gluten sensitivity.

We need a randomized clinical study of the general population to get a better estimate of the magnitude of this condition. As the authors point out, ideally, this would placebo-controlled and “double-blinded”. (Patients would be given gluten or an inert placebo, and neither the patients nor observers would be aware of who was in which group).

A specific diagnostic test for non-celiac gluten sensitivity would be ideal, and would certainly make a clinical study easier to perform. However, this is probably a long way off, since there is little known about the molecular mechanism of the condition, or even if it is a single phenomenon.

The good news is that there may be fewer ethical concerns about performing research studies on gluten sensitivity than on celiac disease. Since consumption of gluten by patients with celiac disease can often cause long-term (and possibly irreversible?) damage to small intestine, there are significant ethical concerns about performing research studies on this population. This is quite different from therapeutic clinical studies in which the patient has the potential for benefitting from the study. These constraints have probably limited the ability to perform large-scale trials of celiac disease. In contrast, since there is less evidence that there are long-term effects of gluten consumption by patients who are “gluten-sensitive”, it seems likely that it will be easier to enroll a larger number of patients, and therefore easier to obtain a clear result.

A consensus report?

The members of this panel are well-recognized in this field, so the recommendations provide a good starting point for a discussion of the nature of gluten sensitivity, how to diagnose it, and hopefully, how to treat it.

However, we were a little concerned about the makeup of this panel, given that this is a health issue for potentially millions of people. It was not stated what criteria were used to choose the experts who participated, what process was used to arrive at a consensus, or how differences were resolved. In our experience, we have yet to see a group of scientists (especially prominent ones) reach a unanimous conclusion on most topics. So, perhaps the “consensus” in the title of the report may be a little premature? While all the members are, indeed, experts in this field, and while it is almost impossible to assemble a perfect panel on a particular date, we believe there were a number of scientists missing from this discussion who have done important work in this field.

This is still an evolving field of research, but the report unfortunately did not highlight areas of disagreement in this field, or propose how such uncertainties could be resolved by well-designed experiments. In addition, there was no discussion about the current consensus on celiac disease diagnosis, or the areas that are still in dispute. This is in contrast to such consensus-building events as the 2004 NIH Consensus Development Conference on Celiac Disease (Ref. 11).

Let us hope that this meeting will not be viewed as the “last word” on this topic, but more of a helpful “opening salvo” designed to provoke a broader discussion about this topic.

Ref. 11: NIH Consensus Development Conference on Celiac Disease. 2004

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