Not-celiac Gluten Sensitivity Clinical Trial
Official title:
Diagnostic Significance of Positive Anti-endomysium Antibodies in the Culture Medium of the Intestinal Biopsies in Not-Celiac Wheat Sensitivity (NCWS)
The most frequent diseases caused by wheat ingestion are T cell-mediated disorders, i.e. celiac disease and immunoglobulin E (IgE)-mediated allergic reactions. However, besides celiac disease and wheat allergy, there are cases of gluten reactions in which neither autoimmune nor IgE-mediated allergic mechanisms are involved. These are generally defined as GS or Not-celiac wheat sensitivity (NCWS). Typically, NCWS diagnosis is made by exclusion, and an elimination diet and an "open challenge" (i.e., the monitored reintroduction of gluten-containing foods) are most often used to evaluate whether health improves or worsen with the elimination or reintroduction of gluten in the diet, respectively. In some circumstances, it is very difficult to distinguish between NCWS and celiac disease. The presence of positive celiac disease specific serum antibodies (anti-tissue transglutaminase (anti-tTG), and anti-endomysium (EmAs) antibodies) is of paramount importance to pose the diagnosis. However, it is well known that the frequency of a positive serology is dependent by the severity of the intestinal damage. Consequently, patients with less severe histology damage (Marsh 1) can have negative serum antibodies. Previous studies had demonstrated that EmAs are produced by the intestinal lymphocytes and previous data from our group showed that EmAs assay in the culture medium of the intestinal biopsies has higher diagnostic accuracy than serum EmAs in diagnosis. Therefore, the aims of our study are to evaluate the clinical-serologic-histology course of NCWS patients, showing positive EmAs assay in the culture medium of the duodenal biopsies at the time of the first evaluation, and the adherence to a gluten-free diet in NCWS patients after a previous full evaluation and a NCWS diagnosis based on double-blinded placebo-controlled (DBPC) challenge.
Gluten is the most important protein component of some grains, notably wheat, rye, and
barley, which are the basis for a variety of wheat-derived alimentary products consumed
throughout the world (bread, pasta, pizza etc). However the "engineering" of
gluten-containing grains created the conditions for human diseases related to gluten
exposure. These forms of gluten intolerance represent a heterogeneous set of conditions,
including celiac disease, wheat allergy and gluten sensitivity (GS), that, combined, seems to
affect about 10% of the general population.
The immune responsiveness to wheat antigens represents a complex process, and its
establishment and maintenance are not completely elucidated. The most frequent diseases
caused by wheat ingestion are T cell-mediated disorders, i.e. celiac disease and IgE-mediated
allergic reactions. However, besides celiac disease and wheat allergy, there are cases of
gluten reactions in which neither autoimmune nor IgE-mediated allergic mechanisms are
involved. These are generally defined as GS or Not-celiac wheat sensitivity (NCWS), because
it is not known what component of the cereals causes the symptoms. Some subjects, who
experience symptoms when eating gluten-containing products and show improvement when
following a gluten-free diet (GFD) may have NCWS instead of celiac disease or wheat allergy.
NCWS patients are unable to tolerate gluten and develop an adverse reaction when eating
gluten, that, usually, and differently from celiac disease, does not lead to small intestinal
damage. Gastrointestinal symptoms in NCWS patients may resemble those associated with celiac
disease, but the overall clinical picture is generally less severe.
Typically, NCWS diagnosis is made by exclusion, and an elimination diet and an "open
challenge" (i.e., the monitored reintroduction of gluten-containing foods) are most often
used to evaluate whether health improves or worsen with the elimination or reintroduction of
gluten in the diet, respectively.
The frequency of NCWS is however still unknown, even though some studies indicated that it is
higher than that of celiac disease; consequently, it is very probable that this condition
have been undiagnosed and under-diagnosed by the physicians for a long time. However, it is
very difficult, in some circumstances, to distinguish between NCWS and celiac disease. In
fact, NCWS patients can show an intestinal histology characterized by intra-epithelial
lymphocytosis (Marsh 1), a finding considered compatible with a celiac disease diagnosis. In
this difficult, possible, celiac disease diagnosis, the presence of positive specific serum
antibodies (anti-tTG and EmAs) is of paramount importance to pose the diagnosis. However, it
is well known that the frequency of a positive serology is dependent by the severity of the
intestinal damage. Consequently, celiac disease patients with less severe histology damage
(Marsh 1) can have negative serum antibodies. Previous studies had demonstrated that EmAs are
produced by the intestinal lymphocytes and previous data from our group showed that EmAs
assay in the culture medium of the intestinal biopsies has higher diagnostic accuracy than
serum EmAs in celiac disease diagnosis.
Therefore, this study has one major aim: 1. Evaluation of the clinical-serologic-histology
course of NCWS patients showing positive EmAs assay in the culture medium of the duodenal
biopsies at the time of the first evaluation; and one secondary aim: 2. Evaluation of the
adherence to a GFD in NCWS patients after a previous full evaluation and a NCWS diagnosis
based on double-blinded placebo-controlled (DBPC) challenge.
For our research, the investigators will select adult patients, both genders, affected with
NCWS (i.e. with symptoms/signs which disappeared on gluten-free diet and worsen on a gluten
containing diet, testing negative for celiac disease, [anti-tTG and EmAs negative, and with
biopsy Marsh 0-1] and wheat allergy [serum specific IgE for wheat negative]).
The investigators will include exclusively patients who had been previously fully evaluated
for suspected celiac disease in our Hospitals (Department of Internal Medicine, Giovanni
Paolo II Hospital of Sciacca, Agrigento, and of Internal Medicine of the University of
Palermo) from January 2002 to December 2012. In all patients NCWS diagnosis had been posed by
means of a DBPC challenge with wheat flour. At the time of the first evaluation, gluten-free
diet was not prescribed, but simply suggested, as these patients were not considered as
suffering from celiac disease.
The investigators will recruit, as a study group, those NCWS patients who had showed a
negative celiac disease serology and Marsh 0-1 duodenal histology, but who had displayed a
positive EmAs assay in the culture medium of the duodenal biopsies (EmA-biopsy). As control
group, NCWS patients with negative EmA-biopsy will be included.
The investigators will include at least one year before evaluated patients. At the time of
the recruitment it will be evaluated both the adherence to the gluten-free diet, by means of
a previously validated dietary form containing a printed list of the most common foods, and
the symptoms score (Gastrointestinal Symptom Rating Scale, GSRS). Then, the investigators
will re-evaluate the patients for a possible celiac disease diagnosis. Serum anti-tTG IgA and
IgG, anti-deamidated peptides of gliadin (DPG) IgA and IgG, and anti-gliadin (AGA) IgA and
IgG will be assayed. Duodenal biopsies will be taken for histological evaluation and for
culture EmAs assay.
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