- Research article
- Open Access
- Open Peer Review
Celiac disease in the Mediterranean area
- Francesca Tucci1,
- Luca Astarita1,
- Abdelhak Abkari2,
- Mona Abu-Zekry3,
- Thomas Attard4,
- Mongi Ben Hariz5,
- José Ramon Bilbao6, 21,
- Ghazalia Boudraa7,
- Samir Boukthir8,
- Stefano Costa9,
- Veselinka Djurisic10,
- Jean-Pierre Hugot11,
- Iñaki Irastorza12, 21,
- Aydan Kansu13,
- Sanja Kolaček14,
- Giuseppe Magazzù9,
- Dušanka Mičetić-Turk15,
- Zrinjka Misak14,
- Eleftheria Roma16,
- Pasqualino Rossi17,
- Selma Terzic18,
- Virtut Velmishi19,
- Carmela Arcidiaco1,
- Renata Auricchio†1 and
- Luigi Greco†1, 20Email author
© Tucci et al.; licensee BioMed Central Ltd. 2014
- Received: 18 July 2013
- Accepted: 30 January 2014
- Published: 11 February 2014
The World Gastroenterology Organization recommends developing national guidelines for the diagnosis of Celiac Disease (CD): hence a profile of the diagnosis of CD in each country is required. We aim to describe a cross-sectional picture of the clinical features and diagnostic facilities in 16 countries of the Mediterranean basin. Since a new ESPGHAN diagnostic protocol was recently published, our secondary aim is to estimate how many cases in the same area could be identified without a small intestinal biopsy.
By a stratified cross-sectional retrospective study design, we examined clinical, histological and laboratory data from 749 consecutive unselected CD children diagnosed by national referral centers.
The vast majority of cases were diagnosed before the age of 10 (median: 5 years), affected by diarrhea, weight loss and food refusal, as expected. Only 59 cases (7.8%) did not suffer of major complaints. Tissue transglutaminase (tTG) assay was available, but one-third of centers reported financial constraints in the regular purchase of the assay kits. 252 cases (33.6%) showed tTG values over 10 times the local normal limit. Endomysial antibodies and HLA typing were routinely available in only half of the centers. CD was mainly diagnosed from small intestinal biopsy, available in all centers. Based on these data, only 154/749 cases (20.5%) would have qualified for a diagnosis of CD without a small intestinal biopsy, according to the new ESPGHAN protocol.
This cross-sectional study of CD in the Mediterranean referral centers offers a puzzling picture of the capacities to deal with the emerging epidemic of CD in the area, giving a substantive support to the World Gastroenterology Organization guidelines.
- Mediterranean area
- Celiac disease
- World gastroenterology organization
- ESPGHAN guidelines
Celiac disease (CD) increased at an unexpected rate in the last two decades [1–3]. It was long considered a problem limited to the wheat-consuming affluent societies of the western world , but it was recently reported in almost every wheat-consuming country worldwide . In the near future, most CD cases are expected to come from Africa, Asia and South America [6–9]. We estimate that more than 5 million cases will occur in the Mediterranean region in the next 10 years. Without a timely diagnosis and appropriate health care, an excess mortality of more than 230,000 cases may be expected in the next decade .
We aim to describe a cross-sectional picture of the clinical features and diagnostic facilities in 16 countries of the Mediterranean basin. Since the new ESPGHAN diagnostic protocol was recently published, our secondary aim is to estimate how many cases could be identified without a small intestinal biopsy in the same area.
Unfortunately Syria, Lebanon and Libya did not participate to the network. Palestine was not able to comply with the requirement for the study. Israel could not obtain the ethical permission to use data already collected for a similar study.
Each referral center from Albania, Algeria, Bosnia Herzegovina, Croatia, Egypt, France, Greece, Italy - Messina and Naples - Malta, Montenegro, Morocco, Slovenia, Spain, Tunisia and Turkey provided a list of 50 unselected consecutive CD cases diagnosed in the center by the best locally available methodologies. Using a standardized form, the clinical and laboratory data leading to the diagnosis were collected for each case. The methods used in each center for the serum assay of tTG were recorded, together with their local normal values. We reviewed the pathology procedure used to evaluate small intestinal biopsy specimens and recorded the methods used to evaluate the HLA haplotype. EMA assay was available in 8/16 centers: due to the subjectivity of the method, we could not obtain a standardized comparable set of results.
According to the WGO diagnostic protocol, tTG are an acceptable proxy of the EMA antibodies, especially in countries with limited resources (“The EMA test requires expert observers, and ELISA tests for detecting tTG antibodies should therefore be recommended in settings with low expertise”). For these reasons, in the analysis, we did not considered the few available EMA values.
Based on the facilities and tests available in each center, for each case we estimated the probability of being diagnosed with CD by the new ESPGHAN diagnostic criteria alone, without small intestinal biopsy. For each case we summed up the number of diagnostic criteria met (clinical symptoms, tTG above 10 folds the upper limit of normal and specific HLA). The sum of the criteria determined the final diagnostic score, which thus ranged from 1 to 3. To reduce large tables, countries were often aggregated within their geographical region (Europe, Balkans, North Africa).
Data analysis was performed using the SPSS 16 software package (SPSS Inc., Chicago, IL, USA). Variables were log transformed when required because of their not normal distribution. Student’s t test and ANOVA were used to compare group means; non parametric tests were used when appropriate; p values <0.05 were considered significant.
Institutional review boards at each collection site approved the study in each country (Albania, Algeria, Bosnia Herzegovina, Croatia, Egypt, France, Greece, Italy, Malta, Montenegro, Morocco, Slovenia, Spain, Tunisia and Turkey) (Additional file 1).
A total of 800 forms were expected by the 16 CD referral centers of the Mediterranean Basin, 50 each, but 51 (6.3%) forms were excluded by the local centers because of missing data, thus 749 (93.7%) CD cases were included in the analysis.
Frequencies of symptoms in the three macro-areas
Presenting symptoms by ages
tTG data were available for 748 cases. The cutoff values of normality in the various countries ranged between 7 and 20 UI/ml, and we normalized the reported raw values for the corresponding threshold of the center. The distribution of tTG values in times the normal local values shows that 252 (36.6%) patients had values 10 times the normal or more and a considerable number, 103 (13.7%), of CD cases were diagnosed by a tTG level not greater than twice the upper limit of the local normal values.
706/749 (94.2%) CD patients underwent a duodenal biopsy. A biopsy report was not provided for 27/43 cases (62.8%) in Albania, for 8/42 cases (19%) in Bosnia Herzegovina, and for 4/36 cases (11.1%) in Egypt. Mild mucosal lesions (T0-T2) were found in 158 patients (22.4%), while 56 (7.9%) patients had partial atrophy (T3a), 492 (69.6%) patients had more severe atrophy (T3b and T3c).
HLA typing was reported for all cases from Greece, Naples, Slovenia and Spain, in 14/42 of cases from Bosnia Herzegovina (33.3%), in 13/50 from Croatia (26%), 16/50 from Messina (Sicily) (22%) and 34/50 from Turkey (68%). HLA results were missing in countries of North Africa (Algeria, Morocco, Tunisia and Egypt), Albania and Montenegro. In conclusion, 368/749 CD cases were genotyped for HLA (49.1%). Of these 285 (77.4%) carry the DQ2 heterodimer, 76 (20%) the DQ8 heterodimer, whereas 7 (1.9%) do not carry either of these molecules.
When could the biopsy be omitted?
Presence of the ESPGHAN diagnostic criteria in the 749 patients
ESPGHAN diagnostic criteria
Given the worldwide increase in CD cases, there is an impelling need to simplify the diagnostic work-up to enable a timely diagnosis [11, 12]. This is particularly true for countries that do not have access to sophisticated techniques. The WGO recommends evaluating the local availability of resources to develop a diagnostic protocol. We now provide a comprehensive picture of the diagnosis of CD in 16 Mediterranean countries. Being in European neighborhood area we evaluated whether the new ESPGHAN diagnostic protocol, which could potentially omit endoscopy and biopsy in a significant number of cases [13, 14], could be applied efficiently in the 16 countries of the Mediterranean Basin who participate to the MEDICEL network. Indeed, in selected populations the “triple test” criteria appear to be helpful: a Spanish study  supports the view that in selected children who are symptomatic and positive for the triple test, CD diagnosis could be established independently of histological findings. Almost all cases here described were diagnosed by a small intestinal biopsy, while the aim of the new ESPGHAN criteria is to reduce the requirement for such and invasive procedures. We shared among the 16 partners the importance of avoiding, at least in a percentage of cases, such an invasive technique.
Unfortunately, in our setting only 20% of suspected CD cases with clear clinical symptoms might qualify for a CD diagnosis without a small intestinal biopsy. This percentage would have increased to about 40% if HLA testing had been available. This limitation is not confined to less equipped countries, but it also applies to many European centers with a long experience in CD diagnosis.
Correlation between tTG and Marsh stages
Unfortunately, in several of the participating referral centers, the laboratory experience to assay the tTG is limited and performed only when financial resources are available. Some laboratories produce semi-quantitative data, increasing the uncertainty of the assessment. One of the objectives of the MEDICEL network is to support the upgrading of local diagnostic resources: hence we are now running ad hoc procedure to standardize the method of antibody assay and to increase the availability of HLA haplotyping by exploiting the new technologies that attempt to bring the test to the point of care [17, 18].
This cross-sectional study provides the first picture of the profile of CD in the countries studied and of the diagnostic resources available in the referral centers. Most cases were symptomatic showing the classical clinical profile. This will probably change significantly in the near future when awareness about CD increases, as has occurred in several European countries [3, 10]. This study suffers from the objective limitation of being a retrospective study. Nevertheless, we needed a cross-sectional picture of the pattern of celiac disease in the area, for which this kind of study is rapidly informative. In the same area we have already started a prospective study in order to validate the findings of this actual study.
In conclusion, this cross-sectional survey provides a multifaceted picture of the CD domain in the Mediterranean area. Being aware of the expanding epidemic of CD over the wheat consuming populations, we hope that simplified diagnostic criteria, possibly avoiding the expensive biopsy, could help to diagnose cases outside the very few referral centers in developing countries. Unfortunately this study does not support this chance to date, but does identify the critical points to be met in order to expand the advantages of the new ESPGHAN diagnostic protocol, especially in countries that need this change the most. These results provide to each participant country required data to develop local strategies according to the WGO recommendations.
We thank the Italian Celiac Society (AIC) and the Association of European Coeliac Societies (AOECS) for their role in the coordination of the participating Mediterranean countries. We are grateful to Jean Ann Gilder (Scientific Communication srl) for writing assistance.
Disclosure of funding
This work was by sponsored by the Ministery of Health of Italy, Direction of International Affairs; Euromed (Episouth) action. Project: “Food-induced diseases – Celiac Disease (Medicel) – Phase II” (CUP n° E61J11000450001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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