Elisabetta Fabiani

Coeliac disease in the year 2000: exploring the iceberg

It is now generally believed that subclinical coeliac disease is common in the general population. We have undertaken screening for this disorder in a school district in central Italy. Screening was divided into three levels: first, IgG and IgA antigliadin antibody (AGA) assay on capillary blood obtained by finger prick; second, AGA plus IgA anti-endomysium antibody (AEA) test and measurement of serum immunoglobulins in venous blood; and third, intestinal biopsy. 3351 students (66% of the eligible population) aged 11-15 years attended first-level screening. 71 (2%) were recalled because of AGA positivity; 18 of these satisfied second-level criteria and underwent intestinal biopsy. Coeliac disease was diagnosed in 11 subjects, most of whom had no serious symptoms. Selective IgA deficiency was found in 4 subjects, 1 of whom also had coeliac disease. The prevalence of subclinical coeliac disease in the study group was 3.28 per 1000. Coeliac disease screening is feasible and involves only slight discomfort to the general population. Such screening can detect large numbers of cases of coeliac disease, which can be treated with a gluten-free diet. Many subclinical cases of coeliac disease would not be detected by screening only a selected group of at-risk patients.

The prevalence of celiac disease in Europe: Results of a centralized, international mass screening project

Abstract Introduction. Although the prevalence of celiac disease (CD) has been extensively investigated in recent years, an accurate estimate of CD frequency in the European population is still lacking. The aims of this study were: 1) to establish accurately the prevalence of CD in a large sample of the European population (Finland, Germany, Italy, and UK), including both children and adults; and 2) to investigate whether the prevalence of CD significantly varies between different areas of the European continent. Materials and methods. Samples were drawn from the four populations. All 29,212 participants were tested for CD by tissue transglutaminase (tTG) antibody test. Positive and border-line findings were further tested for serum endomysial antibodies (EMA). All serological determinations were centrally performed. Small-bowel biopsies were recommended to autoantibody-positive individuals. Previously diagnosed cases were identified. Results. The overall CD prevalence (previously diagnosed plus anti-tTG and EMA positives) was 1.0% (95% CI 0.9–1.1). In subjects aged 30–64 years CD prevalence was 2.4% in Finland (2.0–2.8), 0.3% in Germany (0.1–0.4), and 0.7% in Italy (0.4–1.0). Sixty-eight percent of antibody-positive individuals showed small-bowel mucosal changes typical for CD (Marsh II/III lesion). Conclusions. CD is common in Europe. CD prevalence shows large unexplained differences in adult age across different European countries.

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.

Why is coeliac disease endemic in the people of the Sahara

The prevalence of antiendomysial antibody (AEA) in 989 Saharawi children was 5.6%. Intestinal biopsies in a subsample confirmed that AEA is a marker of coellac disease in people living in a developing country.

Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study.

Objective To investigate the value of serum antitissue transglutaminase IgA antibodies (IgA-TTG) and IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of coeliac disease in cohorts from different geographical areas in Europe. The setting allowed a further comparison between the antibody results and the conventional small-intestinal histology. Methods A total of 144 cases with coeliac disease [median age 19.5 years (range 0.9-81.4)], and 127 disease controls [median age 29.2 years (range 0.5-79.0)], were recruited, on the basis of biopsy, from 13 centres in nine countries. All biopsy specimens were re-evaluated and classified blindly a second time by two investigators. IgA-TTG were determined by ELISA with human recombinant antigen and IgA-EMA by an immunofluorescence test with human umbilical cord as antigen. Results The quality of the biopsy specimens was not acceptable in 29 (10.7%) of 271 cases and a reliable judgement could not be made, mainly due to poor orientation of the samples. The primary clinical diagnosis and the second classification of the biopsy specimens were divergent in nine cases, and one patient was initially enrolled in the wrong group. Thus, 126 coeliac patients and 106 controls, verified by biopsy, remained for final analysis. The sensitivity of IgA-TTG was 94% and IgA-EMA 89%, the specificity was 99% and 98%, respectively. Conclusions Serum IgA-TTG measurement is effective and at least as good as IgA-EMA in the identification of coeliac disease. Due to a high percentage of poor histological specimens, the diagnosis of coeliac disease should not depend only on biopsy, but in addition the clinical picture and serology should be considered.

High prevalence of undiagnosed coeliae disease in 5280 Italian students screened by antigliadin antibodies

Many cases of coeliae disease are currently undiagnosed. We carried out a pilot study on screening for coeliae disease in a school population. The screening protocol consisted of three parts: (1) IgG and IgA antigliadin antibody (AGA) assay; (2) antiendomysium antibody and total serum IgA determinations; (3) jejunal biopsy. A total of 5280 students aged 11‐15 years (71.7% of the eligible population) underwent the first evaluation; 113 subjects performed the second tests and 35 of these needed the third investigation. Coeliae disease was diagnosed in 23 cases, most of which were atypical or silent forms. The prevalence of undiagnosed coeliae disease was 4.36 per 1000 screened subjects (95% CI 2.58‐6.14) and 5.03 per 1000 (95% CI 3.41‐6.65) in the general population. The ratio of known to undiagnosed cases was 1 to 6.4. This high prevalence of undiagnosed coeliae disease raises a number of problems that require further evaluation.

The serum Iga class anti-tissue transglutaminase antibodies in the diagnosis and follow up of coeliac disease. Results of an international multi-centre study

Objectives So far the reliability of the anti-tissue transglutaminase (anti-tTG) test for the diagnosis of coeliac disease has mostly been evaluated using slightly different enzyme-linked immunosorbent assays (ELISAs) in selected and usually small groups of patients. The aims of this study were: (1) to evaluate the reliability of the IgA anti-tTG antibodies for the diagnosis of coeliac disease; and (2) to define the sensitivity and specificity of a commercially available kit for the anti-tTG antibodies’ quantitative determination. Design Each centre in this international multi-centre study collected sera from three groups of subjects: coeliac disease patients at the onset of (1) or on a gluten-free diet for at least 12 months (2); disease and healthy controls (3). Methods The anti-tTG antibodies were determined in duplicate using an ELISA-based commercially available kit (Eu-tTG Eurospital, Trieste, Italy). Results The following overall cases and controls have been enrolled: (1) 399 subjects with active coeliac disease; (2) 351 treated coeliac disease cases; (3) 432 controls. The centralized re-testing was performed on: (1) group a: 176 patients with active coeliac disease (mean anti-tTG, 21 arbitrary units [AU]); (2) group b: 172 treated coeliac disease cases (mean anti-tTG, 5 AU); (3) group c: 206 controls (mean anti-tTG, 3 AU). In active coeliacs, the anti-tTG antibodies showed a significant progressive decrease with age, while in controls an opposite trend was found. In active coeliac disease patients, the anti-tTG antibodies were significantly higher in coeliacs with a grade III enteropathy than in those showing a grade II lesion. In treated coeliacs, the mean anti-tTG values were significantly lower in patients strictly adhering to a gluten-free diet than in those reporting dietary transgressions. The sensitivity and the specificity of the Eu-tTG assay were 90% and 96%, respectively. Conclusion The results of this study show that the commercially available test for the anti-tTG antibodies’ determination is a reproducible and valuable tool for the diagnosis and follow up of coeliac disease.

European multi-centre study on coeliac disease and non-Hodgkin lymphoma.

Introduction Coeliac disease (CD) is associated with an increased risk of non-Hodgkin lymphoma (NHL), but there is little information about whether this is true for clinically silent CD. Objective To investigate the frequency of CD in two European populations; one with NHL and another derived from the general population. Methods A prospective, multi-centre, case–control study in 10 European countries was conducted between May 1998 and April 2001. A total of 1446 consecutive patients with newly diagnosed NHLaged over 18 years was collected. The control group consisted of a population of 9676 individuals who were screened for CD. The number of patients with a previous diagnosis of CD and those with silent CD detected by screening were determined in the two groups. Results The patients with CD had a significantly increased risk of developing NHL [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4–4.9]. This risk was only present in patients with CD diagnosed clinically before the study (OR 3.3, 95% CI 1.4–7.9), but not in those with silent CD detected by screening (OR 1.3, 95% CI 0.6–2.7). Conclusion Patients with CD have an increased risk of developing NHL, although this is lower than previously thought. Clinically silent CD is rare in patients with NHL.

Dietary compliance in screening-detected coeliac disease adolescents

In 1992–94 we screened 6315 students for coeliac disease (CD) by testing antigliadin antibodies (AGA) as the first‐level investigation. We found 28 biopsy‐proven coeliac patients who were invited to start the gluten‐free diet (GFD). The aim of this study was a clinical and laboratory follow‐up in these screening–detected coeliac adolescents. Patients were 17 females and 11 males with a mean age at diagnosis of 12.8 ± 1 years (range 11–14). Mean follow‐up duration time was 23 ± 7 months (range 9–37). Twenty‐three of the 28 screening‐detected coeliac patients came to the control visit, 3 refused the follow‐up and 2 subjects were not found. Twelve patients (52.2%) stated that they never ate any gluten‐containing food, while 11 of them (47.8%) reported occasional transgressions to the diet. GFD acceptance was reported as good (n= 6), moderate (n= 11) or low (n= 6). After starting the GFD, signs of improvement were seen in most patients, such as weight gain, increased height velocity and increased feeling of well‐being. AGA (both IgG and IgA classes) and antiendomysium antibodies (AEA) were normal in 19 subjects, 2 cases had IgG‐AG A and AEA positivity, 1 patient showed abnormal AGA and AEA levels, while isolated IgA‐AGA positivity persisted in 1 case. This study shows that even silent CD cases can clinically benefit from the GFD. The consequences of occasional transgressions to the GFD remain unclear.

Antiendomysium versus Antigliadin Antibodies in Screening the General Population for Coeliac Disease

Background: It has recently been shown that mass screening for coeliac disease, using either the serum antigliadin (AGA) or antiendomysium antibodies (EMA) as screening test, can detect large numbers of cases that had escaped clinical diagnosis. The influence of the diagnostic algorithm on the results of the coeliac screening has not yet been evaluated. Our aim was to compare the validity of the AGA and the EMA protocols in 2096 students living in northwest Sardinia, who took part in a serologic screening for coeliac disease. Methods: The sample included 2096 of 2345 eligible students (89%) aged 11-15 years who underwent serum IgG AGA, IgA AGA, and IgA EMA determinations. Total serum IgA level was measured in sera showing isolated IgG AGA positivity. Subjects showing at least one of the following: a) EMA positivity, b) IgA AGA positivity, or c) IgG AGA positivity and IgA deficiency (<5 mg/dl) were asked to submit to a small-intestinal biopsy. Results: The prevalence of coeliac disease was 19 (16 showing typical enteropathy, 1 potential case, and 2 known cases) of 2096 (0.91%; 95% confidence interval = 0.50-1.31). Seventeen small-intestinal biopsy specimens were needed to confirm 16 cases of manifest coeliac disease (positive predictive value (PPV) = 94%) by the EMA protocol, whereas the AGA protocol required 21 biopsy specimens for 12 cases of coeliac disease (PPV = 57%). None of six IgA-deficient, IgG AGA-positive cases detected by the AGA protocol also had coeliac disease. Conclusions: The EMA protocol is superior to the AGA protocol for mass screening of coeliac disease because of higher sensitivity, decreased need for intestinal biopsy, and possibility to detect potential cases of coeliac disease.BACKGROUND It has recently been shown that mass screening for coeliac disease, using either the serum antigliadin (AGA) or antiendomysium antibodies (EMA) as screening test, can detect large numbers of cases that had escaped clinical diagnosis. The influence of the diagnostic algorithm on the results of the coeliac screening has not yet been evaluated. Our aim was to compare the validity of the AGA and the EMA protocols in 2096 students living in northwest Sardinia, who took part in a serologic screening for coeliac disease. METHODS The sample included 2096 of 2345 eligible students (89%) aged 11-15 years who underwent serum IgG AGA, IgA AGA, and IgA EMA determinations. Total serum IgA level was measured in sera showing isolated IgG AGA positivity. Subjects showing at least one of the following: a) EMA positivity, b) IgA AGA positivity, or c) IgG AGA positivity and IgA deficiency (<5 mg/dl) were asked to submit to a small-intestinal biopsy. RESULTS The prevalence of coeliac disease was 19 (16 showing typical enteropathy, 1 potential case, and 2 known cases) of 2096 (0.91%; 95% confidence interval = 0.50-1.31). Seventeen small-intestinal biopsy specimens were needed to confirm 16 cases of manifest coeliac disease (positive predictive value (PPV) = 94%) by the EMA protocol, whereas the AGA protocol required 21 biopsy specimens for 12 cases of coeliac disease (PPV = 57%). None of six IgA-deficient, IgG AGA-positive cases detected by the AGA protocol also had coeliac disease. CONCLUSIONS The EMA protocol is superior to the AGA protocol for mass screening of coeliac disease because of higher sensitivity, decreased need for intestinal biopsy, and possibility to detect potential cases of coeliac disease.