Francesco Cataldo

The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects

Background: Recent studies suggest that coeliac disease (CD) is one of the commonest, life‐long disorders in Italy. The aims of this multicentre work were: (a) to establish the prevalence of CD on a nationwide basis; and (b) to characterize the CD clinical spectrum in Italy. Patients and methods: Fifteen centres screened 17201 students aged 6–15 years (68.6% of the eligible population) by the combined determination of serum IgG‐ and IgA‐antigliadin antibody (AGA) test; 1289 (7.5%) were IgG and/or IgA‐AGA positive and were recalled for the second‐level investigation; 111 of them met the criteria for the intestinal biopsy: IgA‐AGA positivity and/or AEA positivity or IgG‐AGA positivity plus serum IgA deficiency. Results: Intestinal biopsy was performed on 98 of the 111 subjects. CD was diagnosed in 82 subjects (75 biopsy proven, 7 not biopsied but with associated AGA and AEA positivity). Most of the screening‐detected coeliac patients showed low‐grade intensity illness often associated with decreased psychophysical well‐being. There were two AEA negative cases with associated CD and IgA deficiency. The prevalence of undiagnosed CD was 4.77 × 1000 (95% CI 3.79–5.91), 1 in 210 subjects. The overall prevalence of CD, including known CD cases, was 5.44 × 1000 (95% CI 4.57–6.44), 1 in 184 subjects. The ratio of known to undiagnosed CD cases was 1 in 7. Conclusions: These findings confirm that, in Italy, CD is one of the most common chronic disorders showing a wide and heterogeneous clinical spectrum. Most CD cases remain undiagnosed unless actively searched.

Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study

Background—Selective immunoglobulin A (IgA) deficiency (SIgAD) is associated with coeliac disease (CD). Aim—To make a retrospective study of the association of SIgAD with CD in Italy. Methods—Hospital medical records of 2098 patients consecutively diagnosed as having CD were reviewed. Results—Of 2098 patients with CD, 54 (2.6%) had SIgAD, representing a 10–16-fold increase over that in the population in general. This increase was not influenced by age or geographical factors. Patients with SIgAD had a higher incidence of silent forms (7/54, 13%), recurrent infections (16/54, 29.6%), and atopic diseases (7/54, 13%) than those without. The association with autoimmune and malignant diseases and the outcome after eating a gluten free diet were similar in patients with or without SIgAD. In all patients with SIgAD, antibodies for IgA gliadin and endomysium were absent, but serum levels of IgG anti-gliadin antibodies were high in almost all of them (51/54). Conclusions—Serum IgA should be measured in order to be able to interpret negative results for IgA anti-gliadin antibodies and anti-endomysial antibodies in patients being screened for CD. Since some patients with CD and SIgAD may be negative for IgG anti-gliadin antibodies, an intestinal biopsy should be performed in all suspected cases.

The clinical pattern of subclinical/silent celiac disease: an analysis on 1026 consecutive cases

OBJECTIVE:The demographic, clinical, and epidemiological features of subclinical/silent celiac disease in Italy were analyzed in a multicenter study carried out with the participation of 42 centers, in the years between 1990 and 1994.METHODS:One thousand twenty-six subclinical/silent patients (644 children and 382 adults, 702 women and 324 men) were considered eligible for the study.RESULTS:The prevalence of the subclinical/silent form increased significantly during the study both in adults (p < 0.001) and in children (p < 0.005), but its prevalence was always lower (p < 0.001) in children than in adults. This increase appears more likely due to a greater diagnostic awareness and to a better use of screening than to a higher number of subclinical/silent cases. Whereas in 1990 a significantly higher proportion (p < 0.001) of subclinical/silent celiac patients was diagnosed in Northern Italy rather than in Southern-Insular Italy, both in adults (46.7%vs 17.2%) and in children (22.0%vs 9.0%), in 1994 such a difference was no longer conspicuous. Both in children and in adults, iron-deficiency anemia appeared to be the most frequent extraintestinal symptom, followed by short stature in children and cutaneous lesions of dermatitis herpetiformis in adults. In 25.9% of the cases another disease was present, with a significantly higher frequency (p < 0.05) in adults (30.1%) than in children (20.7%). Diabetes and atopy appeared to be the most frequently associated conditions both in children and in adults.CONCLUSIONS:This study has provided an analysis of the largest series of subclinical/silent celiac disease reported to date. In Italy, this form is most frequently recognized in adults, and prospective studies will clarify whether the lower frequency observed in children is a real or apparent phenomenon.

Genome Search in Celiac Disease

Celiac disease (CD), a malabsorption disorder of the small intestine, results from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the entire genetic susceptibility. To determine the localization of other genetic risk factors, a systematic screening of the genome has been undertaken. The typing information of 281 markers on 110 affected sib pairs and their parents was used to test linkage. Systematic linkage analysis was first performed on 39 pairs in which both sibs had a symptomatic form of CD. Replication of the regions of interest was then carried out on 71 pairs in which one sib had a symptomatic form and the other a silent form of CD. In addition to the HLA loci, our study suggests that a risk factor in 5qter is involved in both forms of CD (symptomatic and silent). Furthermore, a factor on 11qter possibly differentiates the two forms. In contrast, none of the regions recently published was confirmed by the present screening.

Celiac disease and selective immunoglobulin A deficiency

Selective IgA deficiency was observed in 12 of 688 (1.7%) patients with celiac disease who were clinically undistinguishable from patients with celiac disease with normal IgA levels. This high prevalence of IgA deficiency in patients with celiac disease makes serum IgA assay advisable when screening for celiac disease is performed by measurement of antigliadin antibodies or anti-IgA endomysium antibodies. Similarly, subjects with IgA deficiency should be considered at risk of celiac disease.

IgG1 antiendomysium and IgG antitissue transglutaminase (anti-tTG) antibodies in coeliac patients with selective IgA deficiency

BACKGROUND In selective IgA deficiency (IgAD), there is no reliable screening test for coeliac disease (CD). AIM To evaluate the usefulness of IgG1 antiendomysium and IgG antitissue transglutaminase tests for CD diagnosis in IgAD. METHODS IgA and IgG antigliadin antibodies (IgA- and IgG-AGA), IgA and IgG1antiendomysium antibodies (IgA- and IgG1-EMA), and IgA and IgG antitissue transglutaminase (IgA- and IgG-anti-tTG) were assayed in: (a) 20 untreated IgAD/CD patients; (b) 34 IgAD/CD patients on a strict gluten free diet (GFD); (c) 10 IgAD/CD patients not on a strict GFD; (d) 11 untreated CD patients without IgAD; (e) 10 healthy IgAD patients; and (f) 25 healthy controls. RESULTS In all untreated IgAD/CD patients, IgG1-EMA, IgG-anti-tTG, and IgG-AGA were positive whereas IgA antibodies against these antigens were negative. IgAD/CD patients on a strict GFD did not produce IgG-AGA or IgG1-EMA but four of 34 produced IgG anti-tTG. IgAD/CD subjects not on a strict GFD produced IgG-AGA whereas 5/10 and 4/10 were IgG1- EMA and IgG-anti-tTG negative, respectively. Untreated CD patients without IgAD were AGA (IgA and IgG), EMA (IgA and IgG1), and anti-tTG (IgA and IgG) positive. Healthy controls were AGA and EMA negative whereas two of 10 apparently healthy IgAD subjects and one of 25 healthy negative control were IgG-anti-tTG positive. CONCLUSIONS Both IgG1-EMA and IgG-anti-tTG tests appear to be useful for identification of IgAD/CD patients whereas they are less satisfactory for monitoring dietary compliance in these subjects. In addition, our findings seem to suggest that IgG-EMA autoantibodies produced by coeliac patients are mainly of the IgG1 subtype.

Antiendomysium antibodies and coeliac disease: solved and unsolved questions. An Italian multicentre study.

A total of 3783 subjects were enrolled to compare IgA and IgG gliadin antibodies (AGA) with IgA endomysium antibodies (EMA) in coeliac disease (CD). Among 688 children with untreated CD EM A were positive in 93.8%, IgA AGA in 84.9% and IgG AGA in 90.2%. AGA, but not EMA, sensitivity decreased with age. EMA were present in 3.8% of control subjects, IgA AGA in 14.9% and IgG AGA in 34.3%. Follow‐up of 5 of 39 EMA‐positive controls showed flat mucosa. Combined determination of EMA and AGA showed an increased predictive value: if EMA and AGA were both positive, the mucosa was flat in 99.1%, if both were negative, the mucosa was normal in 99.1%. After a gluten‐free diet (GFD), IgA‐AGA disappeared first. Among 21 patients not on a strict GFD and in 194 coeliac patients after challenge, EMA, but not AGA, were always positive. Among 67 first‐degree relatives of coeliacs, the positive predictive value of EMA was 90.6%, IgA AGA 74.3% and IgG AGA 44.6%. In conclusion, EMA screening is an excellent test for the diagnosis and follow‐up of CD, and for identification of its silent and latent forms.Antiendomysium antibodies, coeliac disease

Increased prevalence of autoimmune diseases in first-degree relatives of patients with celiac disease.

BackgroundThe prevalence of autoimmune disorders is increased in patients with celiac disease (CD), and it is unknown whether their first-degree relatives also have a high risk of autoimmune disorders. MethodsTo assess the prevalence of autoimmune diseases in first-degree relatives of CD patients, the authors looked for autoimmune disorders in 225 first-degree relatives of 66 children with CD (group A) and in 232 first-degree relatives of 68 healthy children (group B). For both groups, serologic screening for CD was performed through antiendomysium (EMA) and tissue transglutaminase autoantibodies (tTGAA). EMA- and tTGAA-positive subjects were offered an intestinal biopsy. The age at onset of autoimmune diseases was also recorded in group A. ResultsThe prevalence of autoimmune disorders was significantly (P = 0.028) higher in group A (11 of 225, 4.8%) than in group B (2 of 232, 0.86%). In relatives of CD patients, the prevalence increased with age (&khgr;2 for trend, 43.5;P < 0.0001). Serologic screening for CD was only positive in group A (15 of 225 subjects). An intestinal biopsy was performed in 13 of these 15 relatives (2 refused biopsy). Eleven of 13 had flat mucosa, with subclinical or silent forms of CD. The prevalence of autoimmune diseases in the EMA- and tTGAA-positive relatives of CD patients was significantly higher (3 of 15, 20%;P = 0.028; odds ratio, 6.3; 95% CI, 1/0.21–1/0.11, 4.9–7.6) than in those who were EMA and tTGAA negative (8/210, 3.8%). ConclusionsThe first-degree relatives of CD patients have an increased risk of autoimmune diseases, most likely connected with unrecognized subclinical or silent forms of CD.

Cytokine Genotyping (TNF and IL-10) in Patients With Celiac Disease and Selective IgA Deficiency

OBJECTIVE:Selective IgA deficiency (IgAD) and celiac disease (CD) are frequently associated and share the ancestral haplotype human leukocyte antigen (HLA)-8.1, which is characterized by a peculiar cytokine profile. The aim of this study was to evaluate the role of tumor necrosis factor (TNF) and interleukin (IL)-10 alleles in CD and CD-IgAD.METHODS:The distribution of some biallelic polymorphisms of both cytokine promoters (−308G→A and −863C→A at TNF promoter sequence and −1082G→A, −819C→A, and −592C→T at IL-10 promoter) were typed using biotilinated specific probes in 32 celiac patients, in 34 CD-IgAD patients, and in 96 healthy controls.RESULTS:In CD and CD-IgAD, the −308A allele was significantly more frequent than in controls, whereas no significant differences were observed for the biallelic polymorphisms at the −863 and for the three IL-10 promoter polymorphisms. The evaluation of combined TNF and IL-10 genotypes showed in CD-IgAD a significant reduction of −308G/−1082G homozygous subjects and both in CD and CD-IgAD groups an increase of 308AA/1082GG. Accordingly, CD-IgAD patients positive both for −308A TNF and −1082A IL-10 showed an increase of TNF-α and a reduction of IL-10 serum levels.CONCLUSIONS:Genetically determined increased production of TNF-α and reduction of IL-10 may be relevant for susceptibility to CD, mainly in IgAD, as the different allele expression at TNF and IL-10 loci seems to influence cytokine production profile.

Are food intolerances and allergies increasing in immigrant children coming from developing countries

There are not available data concerning the occurrence, the clinical features and the environmental risk factors for food intolerances and allergies in immigrant children. The aim of the study was to evaluate rates, distribution, clinical features and environmental risk factors for food intolerances and allergies in immigrant children. Hospital records of 4130 patients with celiac disease (CD), cow milk protein intolerance (CMPI) and food allergies (FA) diagnosed in 24 Italian Centres from 1999 to 2001 were retrospectively reviewed, comparing immigrant patients with Italian ones. 78/4130 (1.9%) patients were immigrant: 36/1917 (1.9%) had CD, 24/1370 (1.75%) CMPI and 18/843 (2.1%) FA. They were evenly distributed across Italy and their native areas were: East Europe (23/78), Northern Africa (23/78), Southern Asia (14/78), Saharan and Sub‐Saharan Africa (9/78), Southern America (4/78), Far East (3/7), Middle East (2/78). Despite differences in their origin, the clinical features of immigrant children were similar to the ones of Italian patients and among each ethnic group. The majority of them were born in Italy (57/78) or have been residing in Italy since several years (19/78). All of them had lost dietary habits of the native countries and had acquired those of the Italian childhood population. Food intolerances and allergies are present also in children coming from developing countries, and paediatricians will need to have a full awareness of them because the number of immigrant children in Italy is quickly increasing. The clinical features of food intolerances and allergies appear the same in each ethnic group, despite differences in races. Sharing of dietary habits with the Italian childhood population seems to be an important environmental risk factor.