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Celiac Disease in the General Population: Should We Treat Asymptomatic Cases?

1997; Lippincott Williams & Wilkins; Volume: 24; Linguagem: Inglês

10.1097/00005176-199700001-00004

1536-4801

Carlo Catassi, E Fabiani, I M Rätsch, G V Coppa, P. L. Giorgi,

Helicobacter pylori-related gastroenterology studies

It has become increasingly evident that celiac disease (CD) is more common than previously thought (1). Owing to the diffusion of sensitive serological markers, such as the antigliadin antibody (AGA) and the anti-endomysium antibody (EmA) tests, a number of atypical presentations have been described, and the existence of asymptomatic (silent) CD cases has come to our attention (2-3). This high CD polymorphism poses a number of problems (4). In order to investigate the “celiac iceberg” (5), we conducted a pilot study of the screening for CD by means of the AGA test in a population sample of healthy students living in central Italy. Herein we present the final results of this screening of 6,315 subjects. An estimate of the overall CD prevalence in this age group is reported, together with comment on issues related to CD screening. THE PROJECT “COELIAC DISEASE IN THE YEAR 2000: EXPLORING THE ICEBERG” Patients and Methods Between March 1992 and June 1994, 8,690 students of both sexes, aged 11 to 16 years and attending compulsory secondary school in the provinces of Pesaro-Urbino and Ascoli Piceno (central Italy), were invited to take part in the screening project. There were five known (biopsy-proven) cases of CD in this population. These five patients were on a gluten-free diet and did not take part in the screening. After giving informed consent, 6,315 students were screened for CD (73% of the eligible population). The study group had a mean age of 12.8 ± 1.0 years. The screening procedure has previously been described (6). During school time, samples of whole blood were obtained for the first-level screening test. This was the determination of both serum IgG-AGA and IgA-AGA in either a capillary or venous blood sample. AGA was measured by enzyme-linked immunoassay (Alfagliatest; Eurospital, Trieste, Italy) on duplicate 5-μl samples. Subjects with a positive IgG-AGA and/or IgA-AGA test were recalled for the EmA test and for total serum IgA determination. IgA class EmA was measured by indirect immunofluorescence, using monkey esophagus as the antigenic substrate (Endomisio; Eurospital). The total serum IgA assay was performed in order to rule out a selective IgA deficiency. An intestinal biopsy was finally recommended for subjects fulfilling at least one of the following criteria: (a) a positive EmA test, (b) a positive IgA-AGA test, or (c) a positive IgG-AGA test associated with selective IgA deficiency. The jejunal biopsy was performed at the hospital gastroenterology clinic using a Watson pediatric capsule. The diagnosis of CD was made according to the revised ESPGAN diagnostic criteria (7). Results The first-level AGA screening was normal in 6,177 of 6,315 subjects (97.8%). After the second-level evaluation, screening results were considered negative in 95 of 138 subjects who showed either normal results on the second level tests or isolated IgG-AGA positivity. An intestinal biopsy was performed in 43 of the 44 subjects who met the criteria for the third-level investigation. Only a 12-year-old boy was not available for intestinal biopsy, but he was considered to have CD since he showed positive results in the IgG-AGA, IgA-AGA, and EmA tests. Twenty-eight of these 43 subjects (17 girls, 11 boys) had flat mucosa on intestinal biopsy. Most of these subjects had no major symptoms, and none of them was under medical surveillance (Table 1). Sixteen of the screening-detected cases of CD were also HLA typed, showing the following genetic patterns: DQw2 in 13 cases, DR3 in eight cases, and DR7 in six cases. The prevalence of undiagnosed CD in this study group was one in 218 subjects (4.59 per 1,000; 95% confidence interval [CI], 2.91 to 6.26). The prevalence of CD for the eligible population was calculated on the assumption that disease prevalence was the same in eligible subjects who did not take part in the study. The estimated prevalence of CD in the eligible population (8,690 students), including the five known cases of CD, was one in 193 subjects (5.17 per 1,000; 95% CI = 3.65 to 6.68). The estimated ratio of known to undiagnosed cases of CD in the eligible population was 1:9. SEROLOGICAL CD SCREENING: WHICH TEST? Different serological tests, such as the AGA, EmA, and antireticulin antibody (ARA) assays, are available for CD screening. In our study, the combined IgG-AGA and IgA-AGA determination was chosen because of the high sensitivity and proper standardization of the cutoff values. A large pediatric study of untreated subjects with CD and controls showed a sensitivity of ≥96% and a specificity of 97% for combined IgG-AGA and IgA-AGA measurements (8). Although the EmA test is considered the most reliable screening method for CD at present (9), its applicability to large screening programs is questionable. Patients with selective IgA deficiency cannot be detected by the EmA test, since this is an IgA class antibody. This problem requires consideration, since it has been established that subjects with selective IgA deficiency carry an increased risk of CD. In our study, one patient who was IgG-AGA positive, but IgA-AGA and EmA negative, was found to be affected with both selective IgA deficiency and CD. HOW COMMON IS CD IN THE GENERAL POPULATION? In this study group, which constitutes the largest population sample screened for CD by a single center, the CD prevalence among teenagers living in central Italy was close to one in 200 subjects. Some patients can remain undiagnosed after AGA screening. The prevalence of 1 in 200 subjects in this age category represents the minimum value. In this area, therefore, CD appears to be the most common chronic disorder in this age group; it is seen much more frequently than other pediatric diseases, such as hypothyroidism, type I diabetes mellitus, cystic fibrosis, or familial hypercholesterolemia. In a recent multicenter study, the prevalence of registered CD cases in Italy was about one of 1,000 subjects. Our results clearly show that clinically diagnosed cases represent just the tip of the CD iceberg. It has been reported that CD prevalence changes with time or shows wide variations between neighboring countries, such as Finland and Sweden or Italy and Greece (10). Since the number of undiagnosed people greatly exceeds the number of patients diagnosed with CD, the highly variable CD prevalence found in previous epidemiological surveys could primarily depend on the different strategies adopted for case ascertainment. A NEW IDENTIKIT FOR CD The clinical picture of CD has undergone change. Typical CD manifestations, such as chronic diarrhea or malnutrition, were present in a minority of cases, while vague intestinal complaints, such as poor appetite or recurrent aphtous stomatitis, were not uncommon. Iron deficiency, a well-known CD-associated disorder secondary to jejunal iron malabsorption, was found, with or without anemia, in 16 of 28 patients with CD detected by screening, suggesting that an accurate CD diagnostic workup is mandatory for patients with unexplained iron deficiency, especially when they are resistant to oral iron therapy. We noticed that irritability, tendency to depression, and unsatisfactory school performance were common findings among these patients. However, we did not perform a standardized psychosocial investigation that could clarify this clinical impression. WHY DO MANY PATIENTS WITH CD REMAIN ASYMPTOMATIC? The reason that many CD patients remain symptom free is still unknown and can only be a matter of speculation. It might be that the extent of mucosal damage is smaller in silent than in symptomatic CD. In this case the absorptive defect of the proximal small bowel could have no clinical consequences, owing to the compensatory function of the distal jejunal mucosa. The results of the intestinal permeability test with lactulose-mannitol in our study support this view. While the lactulose-mannitol urinary ratio is usually increased in typical CD (11), 11 of 21 patients with screening-detected CD showed a normal value (12). SHOULD WE TREAT ASYMPTOMATIC CASES? It is our current policy to recommend the standard gluten-free diet for the treatment of silent CD cases, for at least two reasons. First, in our study most patients with apparently silent CD were not completely asymptomatic. This is evident from the follow-up visits, when many patients reported subtle benefits after starting the gluten-free diet. The most common changes were gains in weight and height, appetite and mood amelioration, better school performance, and physical fitness. Second, clinically silent CD causes the same jejunal damage and has the same immunological pattern and genetic background as typical CD. At present we have no reason to suggest a different therapeutic strategy for these patients. A number of long-term CD complications have been described, such as infertility, osteoporosis, and lymphoma (13). The treatment of asymptomatic CD may become primarily an issue of prevention. Further studies are required in this area, because the impact of CD-associated risk is still unclear. CONCLUSION This study confirms that CD is much more common in Italy than previously thought and that most cases remain undiagnosed unless actively identified through serological screening tests. Efforts should be made to improve the understanding of this condition among doctors and other health workers, since this would allow detection of some undiagnosed cases. It also appears advisable to recommend the inclusion of a screening test for CD, such as the AGA or EmA assay, in routine hematological investigations during childhood. Further studies are needed to map the prevalence of CD in different countries.