Increased Prevalence of Celiac Disease in Patients With Dyspepsia FREE

CELIAC DISEASE (CD) is characterized by a wide range of intestinal and/or extraintestinal manifestations that, in susceptible individuals, are attributable to the toxic action of the gluten present in wheat, rye, and barley.¹ As defined according to recent reviews,^2- 3 dyspeptic symptoms are reported by a number of patients with CD⁴ and may represent the only manifestation of a disease that affects 1 in 200 subjects in most series from Western countries^5- 7; the prevalence is similar in Italy.^8- 9 However, despite this, there are no data concerning the prevalence of CD in patients with dyspepsia, to our knowledge. This fact is surprising given that a gluten-free diet is highly successful in normalizing clinical and histologic abnormalities,¹⁰ thus preventing severe and life-threatening CD complications, such as lymphoma or ulcerative jejunoileitis,¹¹ and avoiding further useless examinations and/or empirical management.

The present prospective study was therefore designed to evaluate the prevalence of CD in a large series of patients with dyspepsia who were undergoing duodenal biopsy and endoscopy of the upper gastrointestinal tract (GI).

Between January and June 1998, all the outpatients attending the GI units of 2 tertiary centers in Lombardy (northern Italy) for upper GI tract endoscopy because of dyspeptic symptoms (chronic or recurrent pain or discomfort centered in the upper area of the abdomen) were prospectively studied. Excluded were patients younger than 12 years; those undergoing clinical workup for an upper GI tract disease suggested by previous radiographic or ultrasonographic findings; those referred for malabsorption, suspected celiac disease, or iron deficiency anemia; those receiving regular follow-up for a known disease (eg, peptic ulcer); and those with classic heartburn or acid regurgitation. All patients who fulfilled the inclusion criteria gave their informed consent for upper GI tract endoscopy and histologic sampling. The study was approved by the Ethics Committee of both centers. The endoscopic findings were classified as normal, consistent with peptic lesions (in the presence of esophagitis, mucosal reddening with erosions, or ulcers), positive for polyps and/or tumors, suggestive of CD (in the case of a loss or reduction in duodenal folds, a nodular or mosaic mucosal pattern, or duodenal fold scalloping),^12- 13 or miscellaneous (hiatal hernia, varices, etc). Four duodenal mucosal samples (2 from 2 cm above and 2 from 2 cm below the major duodenal papilla) were obtained from all patients during upper GI tract endoscopy (using GIF-100; Olympus Optical Co, Tokyo, Japan), with further samples being obtained when considered necessary, ie, in the presence of macroscopic appearances consistent with esophagitis, gastritis, and/or duodenitis. The biopsy specimens were oriented, routinely processed, stained with hematoxylin-eosin and periodic acid–Schiff, and blindly examined by two of us (M.T.B. and P.V.) independently. The diagnosis of CD was based on the presence of villous atrophy, crypt hyperplasia, and an increased number of lymphocytes in the epithelium and lamina propria¹⁴; the presence of Helicobacter pylori was also always searched for histologically. All patients with a histologic diagnosis of CD also underwent standard nephelometric serological immunoglobulin determinations and IgA antiendomysium antibody measurements obtained by indirect immunofluorescence (Eurospital, Trieste, Italy) and were put on a gluten-free diet and followed up.

Descriptive statistics (mean, SD, minimum, and maximum) were calculated together with relative risks and 95% confidence intervals.¹⁵

Five hundred thirty-three of the 3019 prospectively evaluated patients complied with the inclusion criteria, but 16 were excluded because of the inadequacy of the duodenal samples taken for histologic processing. The analysis was therefore based on the biopsy specimens obtained from 517 patients, representing 17% of the entire group (207 males and 310 females; mean ± SD age, 49.9 ± 16 years; age range, 14-88 years).

The endoscopic findings were normal in 311 cases (60%), showed peptic lesion(s) in 132 (26%), demonstrated polyp(s) or tumors in 13 (2%), were suggestive of CD in 5 (1%), and were miscellaneous in 56 (11%). Celiac disease was histologically diagnosed in 6 patients (1.2%), 3 of whom had a normal duodenal endoscopic pattern (false-negative results), and 3 of whom had an endoscopic pattern suggestive of CD. The sensitivity of the endoscopic markers for CD was therefore 50%. The loss of duodenal folds in 2 other cases suggested CD, but the diagnosis was not histologically confirmed.

The demographic, endoscopic, histologic, and serological characteristics of the 6 patients with CD (3 diagnosed in Milan and 3 in Como) are shown in Table 1. All 6 patients were antiendomysium antibody positive; their ages ranged from 20 to 46 years (mean±SD age, 31.3 ± 9.5 years); and 5 were female. None of them presented any histologic evidence of H pylori. There was absolute agreement between the 2 pathologists in diagnosing or excluding CD.

The present results indicate that patients with dyspepsia have an increased risk for CD and that the endoscopic duodenal markers suggestive of the disease are not sufficient to confirm or rule out its presence.

Over recent years, in addition to serological markers,¹⁶ increased attention has been given to some endoscopic findings that may be suggestive of CD (eg, loss, reduction, or scalloping of duodenal folds and/or a nodular or mosaic mucosal pattern). The data from different studies indicate a sensitivity of 73% to 100%, a specificity of 83% to 99%, and a positive predictive value of 85% to 91% for the above-mentioned markers.^{12- 13,17- 19} However, some of these results may reflect a selection bias (most of the studies included patients undergoing specific workup for overt malabsorption and/or suspected CD), and the series that included patients without CD were strongly biased because duodenal biopsy specimens were obtained only in the presence of one or more of the so-called typical endoscopic CD markers.

In our study, multiple duodenal samples were obtained from all patients who underwent upper GI endoscopy for dyspepsia, and, despite the long training of the endoscopists involved, the overall diagnostic sensitivity of the endoscopic marker(s) was only 50%.

Celiac disease has a wide spectrum of clinical manifestations, ranging from symptomless to atypical forms and even severe malabsorption,^1,20- 21 and dyspepsia may be one of its symptoms.^4,13 Our data clearly indicate that patients with dyspepsia are at definite risk for CD: its prevalence was more than twice that reported in general populations from the same geographical areas and most Western countries.^5- 9 Interestingly, the subgroup of dyspeptic patients at the highest risk comprised young women: 5 of the 6 patients with CD were women aged 20 to 37 years, and compared with the general population, their relative risk of CD was 3.22 (95% confidence interval, 1.37-7.56). The early diagnosis of CD is advisable because of the high prevalence of the disease and the beneficial effect of a gluten-free diet in decreasing the risk of intestinal lymphoma¹¹ and other complications,^10,22- 23 which worsen the quality of life and lead to an increase in costs owing to useless examinations or supportive therapies.^24- 25

Our results suggest that the workup of patients with dyspepsia could be modified. It is well known that an organic cause is found in only 40% of cases²⁶ and that the findings of clinical history and physical examination cannot reliably help in differentiating organic from functional dyspepsia,²⁷ which explains the current controversy as to whether all patients with dyspepsia should undergo early endoscopy or start with empirical therapy.^27- 30 In fact, although 30% to 60% of these patients have H pylori–related gastritis, there is still uncertainty as to whether the infection is responsible for the symptoms or whether eradication treatment induces a clinical improvement.^31- 33

Although it is beyond the scope of this study to discuss the approach to dyspepsia (which needs to be evaluated by means of prospective studies based on cost-benefit analysis), we believe that our results justify modifying the guidelines recommended by recently reported consensus statements.²⁷ In the case of patients with dyspepsia who are older than 45 years or those considered to be at risk for gastric cancer and for whom early endoscopy is advisable, it would be useful to obtain additional duodenal samples because of the possibility of false-negative endoscopic results: this simple procedure can rule out CD on the basis of subsequent histologic findings. Patients who are younger than 45 years and who show no signs or symptoms of an underlying organic disorder should be serologically examined for CD before costly and empirical treatment is begun. As shown by our results and those of a study based on data from an open-access endoscopy unit,³⁴ this approach seems to be particularly appropriate for females. Serological CD screening can be based on the determination of antiendomysium antibodies, which, in addition to being the most sensitive and specific test currently available,³⁵ is relatively inexpensive, even for screening large series of patients, because of the possibility of detecting antiendomysium antibodies using human umbilical cord or umbilical vein endothelial cells.³⁶

In conclusion, serological CD screening should be considered in the early diagnostic workup of patients with dyspepsia (especially female patients) who are younger than 45 years to ensure that such a frequent disorder as CD is not missed.

Accepted for publication October 14, 1999.

This study was supported in part by grants from the CARIPLO Foundation, the Associazione Amici della Gastroenterologia Granelli, and the Associazione Italiana Celiachia, Milan, Italy.

The authors are indebted to Bruno M. Cesana, MD (Epidemiology Unit, IRCCS Ospedale Maggiore, Milan, Italy), for performing the statistical analysis and to Claudia Terrani for processing the histologic samples (Cattedra di Gastroenterologia, IRCCS Ospedale Maggiore).

Reprints: Maria Teresa Bardella, MD, Cattedra di Gastroenterologia, Padiglione Granelli, Via F. Sforza 35, 20122 Milano, Italy.