Coeliac disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals and characterised by the presence of a variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes, and enteropathy.1,2 Current data suggest that patients with mild enteropathy (not villous atrophy) may present with gluten sensitive symptoms and complications, and that they may show good clinical and histological response to a gluten-free diet (GFD).3–8 The broader term gluten-sensitive enteropathy (GSE) comprises the whole spectrum of gluten-dependent mucosal histopathological lesions, which range from normal villous architecture with intraepithelial lymphocytosis as the only abnormality to total villous atrophy.9 Patients with minimal immunopathological changes in the intestine and gluten-sensitive symptoms have been diagnosed recently as suffering from non-coeliac gluten-sensitivity.10

Dyspepsia is a common symptom of GSE and may be present in up to 60% of these patients, including those with mild enteropathy.11,12 The prevalence of CD, based on the presence of intestinal villous atrophy, in patients with dyspepsia is significantly higher than that in the general population, occurring at a rate of 1.2–5.8%.13–20 This may be because patients with CD frequently experience gastrointestinal motility disturbances.21–23 These motility disorders of the upper gastrointestinal tract may contribute to the development of symptoms such as postprandial fullness, bloating, flatulence, distension, nausea and/or vomiting, as well as regurgitation and heartburn.19,24 To the best of our knowledge, there have been no published reports on the prevalence of the whole spectrum of GSE in patients with dyspepsia.

Therefore, the aim of the present study was to investigate the prevalence of GSE, including mild enteropathy, in patients with dysmotility-like dyspepsia symptoms (DLDS) and normal upper gastrointestinal (GI) endoscopy results.

From January to December 2007, we performed a total of 1565 upper GI endoscopies, 501 (32%) of which were performed for dyspepsia evaluation. Of the 335 patients with dyspepsia and normal upper GI endoscopy, 142 with DLDS were included for this study (mean age 45.8±15 years; 73.9% females). Fifty-one of these 142 patients (35.9%) had enteropathy, including 4 (2.8%) with subtotal villous atrophy (Marsh type 3b), 24 (16.9%) with partial villous atrophy (Marsh type 3a), 3 (2.1%) with hyperplasic crypts (Marsh type 2), and 20 (14.1%) with lymphocytic enteropathy (Marsh type 1). None of the patients presented total villous atrophy (Fig. 1).

Figure 1.

Selection of dyspepsia patients at the endoscopy unit.

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When we compared patients with and without enteropathy, we observed that patients with duodenal histopathological lesions were younger (42.4 vs. 47.7 years, P<0.05), and those patients more frequently had hypertransaminasemia (13.7% vs. 3.3%, P<0.05), and a previous diagnosis of gastro-oesophageal reflux disease (27.5% vs. 13.2%, P<0.05)(Table 1). Regarding the symptoms, only diarrhoea was significantly more common in patients with duodenal histopathological lesions vs. those without (31.4% vs. 14.3%, P<0.05), and only abdominal distension was more frequent in patients with Marsh type 3 lesions than that in patients with Marsh type 1 or type 2 lesions (75% vs. 43.5%, P<0.05) (Table 2).

Gluten-free diet

Fig. 2 presents the clinical evolution and final diagnoses of the 51 patients with enteropathy. Thirty-four of 37 (91.9%) patients who started a gluten-free diet improved their dyspeptic symptoms (78.6% Marsh type 1, 100% Marsh type 2, 100% Marsh type 3a, 100% Marsh type 3b), and 26 of 32 (81%) patients who accepted and received a second upper GI endoscopy presented an improvement of histopathological lesions (72.7% Marsh type 1, 100% Marsh type 2, 93.8% Marsh type 3a, 50% Marsh type 3b). In these patients, duodenal intraepithelial lymphocytes counts also improved following the GFD. The IELs counts and means decreased from 36±10.2 to 19.2±11.9 (P<0.001, Fig. 3). Two patients presenting with Marsh type 3b lesions, the presence of t-TGA and without histopathological improvement, were also diagnosed with GSE based on their clinical and serological responses (i.e., normalization of t-TGA) to the GFD. A final GSE diagnosis was thus established in 28 of 142 patients (19.7%). Table 4 shows serology, HLA-DQ type, histopathology and H. pylori diagnosis in these patients.

Figure 2.

Clinical evolution and final diagnosis of the 51 patients with enteropathy (GFD: gluten-free diet; IELs: duodenal intraepithelial lymphocytes).

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Figure 3.

Duodenal intraepithelial lymphocytes (IELs) before and after implementation of a gluten-free diet (GFD).

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Table 4.

Serology, HLA-DQ type, histopathology and H. pylori diagnosis in gluten-sensitive enteropathy patients.

ID	Age	Sex	Marsh	t-TGA	HLA-DQ type	IELs	IELs post GFD	Marsh post GFD	Histologic relief	H. pylori
1	24	Male	1	Neg	DQ2 heterozygous/DQ8	28	6	0	Yes	Neg
2	47	Female	1	Neg	DQ2 heterozygous/DQ8	65	8	0	Yes	Neg
3	24	Female	1	Neg	DQ2 homozygous	40	28	1	Yes	Pos
4	37	Female	1	Neg	DQ2 homozygous	66	31	1	Yes	Pos
5	63	Female	1	Neg	DQ2 homozygous	26	15	0	Yes	Pos
6	22	Female	1	Neg	DQ2 homozygous	40	24	1	Yes	Pos
7	62	Female	1	Neg	DQ2 homozygous/DQ8	36	10	0	Yes	Pos
8	31	Female	1	Neg	DQ2 homozygous	50	9	0	Yes	Pos
9	50	Female	2	Neg	DQ2 homozygous	25	18	0	Yes	Pos
10	23	Female	3a	–	DQ2 homozygous	38	13	0	Yes	Pos
11	50	Female	3a	Neg	DQ2 heterozygous	25	20	0	Yes	Neg
12	56	Female	3a	Neg	DQ2 heterozygous	25	16	0	Yes	–
13	20	Male	3a	Neg	DQ2 heterozygous	30	8	0	Yes	Neg
14	44	Male	3a	Neg	DQ2 heterozygous	40	15	0	Yes	Neg
15	49	Female	3a	Neg	DQ8	30	12	0	Yes	Pos
16	29	Female	3a	Neg	DQ8	25	10	0	Yes	Pos
17	54	Female	3a	Neg	DQ2 heterozygous	40	6	0	Yes	Neg
18	29	Male	3a	Neg	DQ2 heterozygous/DQ8	35	8	0	Yes	Pos
19	50	Male	3a	Neg	DQ2 homozygous	38	15	0	Yes	Neg
20	49	Male	3a	–	DQ2 homozygous	36	9	0	Yes	Neg
21	62	Female	3a	Neg	DQ2 homozygous/DQ8	38	8	0	Yes	Neg
22	34	Female	3a	Neg	DQ2 homozygous/DQ8	30	17	0	Yes	–
23	55	Female	3a	Neg	DQ2 homozygous	26	27	1	Yes	Pos
24	49	Female	3a	Neg	DQ2 homozygous	42	26	1	Yes	Neg
25	25	Female	3b	Neg	–	38	7	0	Yes	Neg
26	64	Female	3b	Neg	DQ2 heterozygous	38	27	1	Yes	Neg
27	35	Female	3b	Pos	DQ2 heterozygous	40	38	3b	Noa	Pos
28	24	Female	3b	Pos	DQ2 heterozygous	43	54	3b	Noa	Neg

t-TGA: IgA-tissue transglutaminase antibodies; IELs: duodenal intraepithelial lymphocytes; GFD: gluten-free diet.

a

These patients presented clinical improvement and normalization of t-TGA after GFD.

Gluten-sensitive enteropathy has a wide and heterogeneous spectrum of clinical manifestations, ranging from symptomless manifestations to the classical gastrointestinal form with diarrhoea and weight loss with a great variety of atypical clinical manifestations in between, such as anaemia, osteopenia, dermatitis, abdominal pain, amongst others.30 Dyspepsia is also a common symptom that may be present in up to 60% of GSE patients.11,12,24 Moreover, the prevalence of CD, based on the presence of intestinal villous atrophy, in patients with dyspepsia is significantly higher than that in the general population, occurring at a rate that varies from 1.2 to 5.8%.13–20

In the present study, we found a higher prevalence of GSE (19.7%) than that found in previous studies. This unexpected prevalence can be explained by several reasons. Firstly, we included a select subgroup of patients with dyspepsia (namely, those with dysmotility symptoms). All these patients were referred to the endoscopy unit for etiologic diagnosis of dyspepsia, allowing us to include patients in real clinical practice. Secondly, in contrast to previous studies the presence of intestinal villous atrophy and serologic markers were not considered to be necessary criteria for the final diagnosis of GSE. In addition, our pathologists processed the duodenal specimens using CD3 lymphocytic immunophenotyping, a useful diagnostic tool for increasing the likelihood of detecting of lymphocytic enteropathy, especially when atrophy is absent.26

Why have we chosen to include only patients with dyspepsia-like dysmotility symptoms in this study? Patients with GSE frequently have gastrointestinal motor disturbances. There are studies that have shown a delay in oesophageal transit, gastric and gallbladder emptying, in addition to orocecal transit time compared to colonic transit.21 These motility disorders of the upper gastrointestinal tract could contribute to the development of symptoms such as postprandial fullness, bloating, flatulence, distension, nausea and/or vomiting, as well as regurgitation and heartburn.19,24 Based on these reports, we thought that those patients with dyspepsia and dysmotility symptoms may be a risk group for GSE. Motility disorders in patients with GSE have been related to complex interactions among the reduced absorption of certain food constituents (for example, fat or starch), a dysfunction in the autonomic nervous system, and derangements of the secretion of several hormones such as cholecystokinin, neurotensin, plasma peptide YY, ghrelin and somatostatin. Fortunately, most of these changes usually disappear after a GFD is implemented.22,23,31–33

Why have we considered patients with mild enteropathy for the diagnosis of GSE in this study? Current data suggest that patients with Marsh types 1–2 lesions and testing positive for endomysial antibodies may suffer from GI symptoms and complications, such as abnormal bone mineral density, as frequently as patients with overt villous atrophy.34,35 Patients with mild enteropathy and negative coeliac serology may also have gluten-sensitive symptoms and complications, such as abdominal pain, distension, diarrhoea, anaemia, osteopenia or hypertransaminasemia.4 Furthermore, several prospective, although not controlled, studies have suggested that most of these patients may show good clinical and histological responses to a GFD.5–8

However, there are conditions other than GSE in which a duodenal intraepithelial lymphocytosis is possible.36,37 Examples of these include H. pylori infection, non-steroidal anti-inflammatory drugs, peptic duodenitis, small intestinal bacterial overgrowth, food protein intolerance (e.g., cow's milk, peanuts and eggs), tropical sprue, autoimmune disorders, oeosinophilic gastroenteritis, Crohn's disease, lymphocytic colitis and common variable immunodeficiency.9 In the present study, most patients had mild histological lesions and negative coeliac serology, and not all these were finally diagnosed with GSE (Fig. 2). According to the recommendation of Collin et al.,29 we have taken into account further evidence in order to diagnose GSE in these patients with borderline enteropathy. Firstly, we performed tests for immunogenetic markers (HLA DQ2 or DQ8) and for specific antibodies (t-TGA). HLA-DQ2 and DQ8 genotyping has a very high negative predictive value for coeliac disease.38,39 If one of these genetic or serologic markers was positive, we offered the patient the opportunity to start a GFD. Secondly, we proved gluten dependence based on the improvement of symptoms and histologic inflammation at an 18-month follow-up. A final GSE diagnosis was established in those patients who improved their symptoms and histopathological or serology abnormalities after undertaking the GFD. The subset characterization of γδ+ IELs and the immunohistologic detection of IgA anti-transglutaminase subepithelial deposits may offer additional value for the diagnosis of GSE but these techniques are not straightforward for use in clinical practice.40,41

Despite the indication in previous studies of the excellent sensitivity and specificity of serology for GSE diagnosis, we found a surprisingly low positivity when testing for t-TGA (7.7%). This may be explained by the fact that the prevalence of t-TGA may be correlated with the degree of intestinal damage; indeed, it has been reported that these antibodies often remain negative in partial villous atrophy or in the absence of atrophy.42,43 In our study, the great majority of patients had only mild enteropathy. In these patients, positive serum antibodies were extremely low (6.7%) in contrast with patients with subtotal villous atrophy (50%). Consequently, the negativity of the serologic test in the cases of mild enteropathy does not rule out GSE, and these tests performed without histologic evaluation may underestimate the real prevalence of GSE. For this reason, duodenal biopsies are still recommended in patients with strong clinical suspicion of GSE, even if serologic testing is negative.1,44

In view of these results, a change could be suggested in the diagnosis workup for patients with dyspepsia. According to the Roma III criteria, functional dyspepsia is defined as the presence of epigastric pain or burning, postprandial fullness or early satiation in the absence of an underlying organic disease likely to explain the symptoms.25 Upper GI endoscopy is the gold standard for excluding an organic cause of dyspepsia. However, the absence of a structural disease at an upper GI endoscopy is not enough to exclude an organic cause of dyspepsia, such as GSE, the diagnosis of which is based on the presence of histopathological small intestinal mucosal damage. Consequently, duodenal biopsies might improve the etiologic diagnoses in patients presenting dysmotility-like dyspepsia (or postprandial distress syndrome according to Roma III criteria) when an upper GI endoscopy does not provide evidence of a structural disease explaining the symptoms. However, the present study has several shortcomings that may have limited the possible clinical application of these results. Firstly, we did not take biopsies from all dyspepsia patients who underwent endoscopy; thus, we did not have a control group. Secondly, the data from the patients who received a GFD were uncontrolled. Consequently, we cannot definitively rule out a placebo effect for the positive response. Although we provided compelling evidence of clinical and histopathological responses to the GFD, we did not give a subsequent gluten challenge to the patients. Therefore, it will be necessary to confirm these preliminary results in randomized, therapeutic trials to determine whether dyspepsia patients with mild enteropathy and without positive coeliac serology will benefit from a GFD.

In conclusion, the present study shows that GSE can be a frequent and unsuspected cause of postprandial distress or dysmotility-like dyspepsia. If these results are confirmed in randomized, controlled clinical studies, duodenal biopsies with CD3 immunophenotyping should be considered as part of the approach for determining a diagnosis of dyspepsia if there is no evidence for a structural disease that could explain the symptoms at the time of an upper GI endoscopy.

Writing support was provided by American Journal Experts and funded by INDOGASTRO foundation.

The authors have no conflicts of interest to declare.