The Science of Gluten-Free Foods and Beverages

THE EPIDEMIOLOGY OF CELIAC DISEASE Carlo Catassi1,2 and Surender Kumar Yachha3 Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy

1

Center For Celiac Research, University of Maryland School of Medicine, Baltimore, MD, United States

2

Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

3

SUMMARY Celiac disease (CD) is one of the most common lifelong disorders in countries populated by individuals of European origin, affecting approximately 1% of the general population. CD is also a common disease in North Africa, the Middle East, and India. The huge prevalence of CD in the Saharawi people (5.6%) is probably related to their strong genetic predisposition and abrupt dietary change during the last centuries. In developing countries, CD is sometimes a severe disease, characterized by chronic diarrhea, stunting, anemia, and increased mortality. Further studies are needed to quantify the incidence of CD in apparently “celiac-free” areas such as sub-Saharan Africa and the Far East. In many developing countries, the frequency of CD is likely to increase in the near future, given the diffuse tendency to adopt Western, gluten-rich diets. Because most cases escape diagnosis all over the world, an effort should be made to increase the awareness of CD polymorphism. A cost-effective case-finding policy could significantly reduce the morbidity and mortality associated with untreated disease.

INTRODUCTION In the past, CD was considered a rare disorder, affecting mostly individuals of European origin, and usually characterized by onset during the first years of life. At that time, the diagnosis was entirely based on the detection of typical gastrointestinal symptoms and confirmation by small intestinal biopsy. The increasing use of highly sensitive and specific serological tools, first the antigliadin (AGA) and later the antiendomysium (EMA) and the anti-transglutaminase (tTG) antibodies, showed an unsuspected frequency of clinically atypical or even silent forms of CD. Using these sensitive and simple tests, a huge number of studies have recently shown that 1

2 The Science of Gluten-Free Foods and Beverages Table 1. Frequency (%) of selected CD predisposing haplotypes in different populations.

Population Saharawi Sardinia Iran Turkey United States Algeria Scandinavia North India Italy Cameroon

DQ2 (cis)

DQ8

Population

23.0 22.4 20.0 18.0 13.1 11.2 11.0 09.0 09.0 09.0

02.7 05.0 12.0 22.0 04.2 02.2 15.0 15.6 02.0 00.6

South African blacks Inuit Gypsy Mongolia North Am. Indians Japan Mexico Cayapa Bushman Highlanders (PNG)

DQ2 (cis)

DQ8

6.2 6.1 6.0 5.2 4.5 0.6 00.

00.

00.

00.

02.8 000.

000.

04.4 25.3 07.6 28.3 410.

30.2 000.

CD is one of the most common lifelong disorders affecting mankind all over the world. This widespread diffusion is not surprising at all, given that causal factors, e.g., human leukocyte antigen (HLA)-predisposing genotypes (DQ2 and DQ8) and consumption of gluten-containing cereals, show a worldwide distribution (Table 1).

CD is not only common in developed countries, but it is increasingly reported in areas of the developing world, especially North Africa, the Middle East, and India.

Furthermore, CD contributes substantially to childhood morbidity and mortality in many developing countries (Fasano and Catassi, 2001).

The aim of this chapter is to present an updated picture of CD epidemiology in both the general population and at-risk groups. The knowledge of CD geographical distribution can help to clarify the complex interaction between genetic and environmental factors underlying this multifactorial disorder.

CD PREVALENCE IN THE GENERAL POPULATION In countries mostly populated by individuals of European origin Italy was the homeland of the new “era” of CD epidemiology during the early 1990s. On a sample of 17,201 healthy Italian students, we showed that CD is much more common than previously thought. We also showed that most atypical cases remain undiagnosed unless they are actively sought out by serological screening (Catassi et al., 1996). The prevalence of active CD in screened subjects was 4.77 per 1,000, or 1 in 210 subjects. The overall prevalence of CD (including known CD cases) was 5.44 per 1,000, or 1 in 184 subjects. Remarkably, the ratio of known (previously diagnosed) to undiagnosed CD cases was as high as 1:7. These results pointed to the existence of a “celiac iceberg,” with a minority of cases being diagnosed on clinical ground (the “tip” of the iceberg) and a larger portion remaining undiagnosed unless actively searched for by serological screening (the “submerged” portion). The wide spectrum of clinical presentation and poor awareness of CD among doctors were (and still are) the main reasons for underdiagnosis.

Serological screenings performed on general population samples confirmed that the prevalence of CD in Europe is high (Csizmadia et al., 1999; Henker et al., 2002; Ivarsson et al., 1999; Korponay-Szabo et al., 1999; Riestra et al., 2000; Volta et al., 2001; West et al., 2003), mostly ranging between 0.4 and 0.75% of the general population, with a trend toward higher figures (1% or more) among groups that have been genetically isolated, such as in Northern Ireland (Johnston et al., 1998), Finland (Mäki et al., 2003), and Sardinia (Meloni et al., 1999). A large, international,

Catassi and Yachha 3

multicenter study investigated a wide population sample in four different European countries: Finland (n = 6,403 adults), Northern Ireland (n = 1,975 children + 4,656 adults), Germany (n = 8,806 adults), and Italy (n = 4,779 adults + 2,649 children).

The prevalence of EMA positivity (roughly equivalent to CD prevalence) was about 2.0% in Finland, 1.2% in Italy, 0.9% in Northern Ireland, and 0.3% in Germany. This study confirmed that many CD cases would remain undetected without active serological screening. In addition to confirming that CD is a very common disorder in the European Union, wide and unexplained variations between countries (e.g., the sevenfold difference in CD prevalence between Finland and Germany) were also disclosed (Mustalahti, 2004).

Until recently, CD was generally perceived to be less common in North America than in Europe. This misconception has been disproven by a large U.S. prevalence study involving 4,126 subjects sampled from the general population (Fasano et al., 2003). The overall prevalence of CD in this U.S. population sample was 1:133, actually overlapping the European figures. Similar disease frequencies have been reported from other developed countries populated mostly by individuals of European origin, such as Canada, Australia, and New Zealand. The presence of CD is long established in many South American countries that are populated mostly by individuals of European origin. Among Brazilian blood donors, the prevalence of CD ranged between 1:681 (Gandolfi et al., 2000) and 1:214 (Oliveira et al., 2007).

It is worth noting that studies on blood donors tend to underestimate the prevalence of CD, because these individuals represent the healthiest segment of the population and are mostly males (while CD is more common among women). In Argentina, Gomez et al. found an overall prevalence of 1 in 167 among 2,000 adults involved in prenuptial examinations (Gomez et al., 2001).

It is interesting to note that the prevalence of CD seems to be increasing in developed countries. The total prevalence of CD doubled in Finland during a period of 20 years (from 1.05% in 1978–1980 to 1.99% in 2000–2001) and the increase cannot be attributed to the better detection rate. The reasons for such a remarkable increase in morbidity are largely unknown. According to the hygiene hypothesis, the main factor underlying the increased prevalence of autoimmune diseases is the reduction in the incidence of infectious diseases. An early childhood infection or normal establishment of indigenous intestinal microbiota could down-regulate immunity and suppress different autoimmune disorders. Alternatively, the increased CD prevalence could be related to changes in environmental factors influencing the risk of CD development, such as the duration of breast feeding and age at gluten introduction (Lohi et al., 2007).

In countries mostly populated by individuals of non-European origin The highest CD prevalence in the world has been described in an African population originally living in Western Sahara, the Saharawi, of Arab-Berber origin. In a sample of 990 Saharawi children screened by EMA testing and intestinal biopsy, we found a CD prevalence of 5.6%, which is almost 10 times higher than in most European countries (Catassi et al., 1999). The reasons for this spiking CD frequency are unclear, but it could be primarily related to genetic factors, given the high level of consanguinity of this population. The main susceptibility genotypes, HLA-DQ2 and -DQ8, exhibit one of the highest frequencies in the world in the

4 The Science of Gluten-Free Foods and Beverages

general background Saharawi population (Catassi et al., 2001). Gluten consumption is very high as well, since wheat flour is the staple food of the Saharawi refugees.

CD in the Saharawi children can be a severe disease, characterized by chronic diarrhea, stunting, anemia, and increased mortality.

We have recently completed a screening project on school children in Cairo, Egypt (Abu-Zekry et al., 2008). We investigated a sample of the general pediatric population (1,500 subjects: 656 females and 844 males; age range 7 months to 18 years, median: 8.0 years) (group A), 150 children (age range 6 months to 13 years, median age: 16 months) admitted for diarrhea or failure to thrive (group B), and 250 children and adolescents affected with type 1 diabetes (group C). The screening test was serum class A anti-transglutaminase (anti-tTG) antibody; IgA antiendomysium, total IgA, IgG anti-tTG, and small bowel biopsy were performed for confirmation of diagnosis. In group A, 8 children fulfilled the criteria for CD diagnosis. The prevalence of CD was at least 1 in 187 subjects (0.53%). In group B, there were 7 children with CD out of 150 (4.7%). In group C, there were 16 out of 250 sera that resulted positive to both the IgA anti-tTG and the EMA test (6.4%).

We concluded that CD is a frequent disorder among Egyptian children, both in the general population and in at-risk groups. Most CD patients remain currently undiagnosed and are exposed to the risk of late manifestations and complications, and therefore, increased awareness of CD is urgently required in this country.

Besides Western Sahara and Egypt, there are no data on the frequency of CD in the general African population. However, indirect evidence suggests that CD is not a rare disorder in northern African countries. Large series of clinically diagnosed patients have been reported from Algeria, Tunisia, and Libya. Furthermore, CD is one of the commonest disorders diagnosed in children born from North African immigrants in France and Italy.

The Middle East holds a special place in the history of CD. Domestication of ancient grains began in Neolithic settlements from wild progenitors Triticum monococcum bocoticcum and T. monococcum uratru in the northeastern region (Turkey, Iran, and Iraq) and T. turgidum dicoccoides in the southwestern region (Israel/Palestine, Syria, and Lebanon) of the so called “Fertile Crescent� area. This extends from the Mediterranean coast on its western extreme to the great Tigris-Euphrates plain eastward. Cultivation of wheat and barley was first exploited and intensively developed in the Levant and western Zagros (Iran) some 10,000 to 12,000 years ago. From the Fertile Crescent, farming spread and reached western Europe some 6,000 years ago. During the 1980s, Simoons theorized that this pattern of agriculture spreading could explain the higher CD incidence in some Western countries, particularly Ireland. While mapping the prevalence of HLA-B8 antigen (the first HLA antigen known to be associated with CD) across Europe, he noted an eastwest gradient, with a consistent increase in antigen frequency with decreasing length of time since farming was adopted. Simoons then hypothesized that the HLA-B8 antigen may have once been prevalent throughout pre-agricultural Europe. According to this theory, spreading of wheat consumption exerted a negative selective pressure on CD-associated genes, such as the HLA-B8. Higher B8 frequency in northeastern Europe, and consequently higher CD frequency, was therefore attributed to a lack of exposure to cereals until relatively recently (Simoons, 1981). This theory did not survive the recent developments in both CD genetics and epidemiology. On one side, it is now well established that the main genetic predisposition to CD is not linked to HLA-B8 but to some DQ genotypes (DQ2 and

Catassi and Yachha 5

DQ8) that are in linkage disequilibrium with B8. Neither DQ2 nor DQ8 show any clear-cut east-west prevalence gradient. On the other hand, the overall CD prevalence is not lower in Middle Eastern countries than in Europe, as should be the case if the longer history of agriculture tended to eliminate the genetic backbone predisposing to CD. Rather, CD is a frequent disorder in the Middle East and along the “silk road” countries. Indeed, one country with a higher prevalence of CD in blood donors is Iran (1 in 167). In the same country, 12% of cases originally diagnosed as irritable bowel syndrome for many years are actually CD (Shahbazkhani et al., 2003). In studies from Iran, Iraq, Saudi Arabia, and Kuwait, CD accounted for 20 and 18.5% of cases with chronic diarrhea in adults and children, respectively. In a study from Jordan, the high incidence of CD was related to the large wheat consumption of the population (135 kg/head/year).

With the availability of improved and more accessible diagnostic tools, CD is being more frequently recognized in India, in both children and adults. There were 130 CD cases reported from India in 1966–2000 versus 517 in 2001–2005. The major factors that resulted in increased reports of CD from India were the use of serologic testing to overcome diagnostic overlap with tropical sprue, tuberculosis, and small bowel bacterial overgrowth. CD constituted 26% (35/137) of all malabsorption syndrome cases in Indian children (91% cases >2 years of age) (Yachha et al., 1993). Furthermore, CD was responsible for 16.6% of the 246 cases of chronic diarrhea (Mohindra et al., 2001). In 9% of Indian adults with malabsorption syndrome, the final diagnosis was CD (Ranjan et al., 2004). By using a case-finding approach (serological testing on symptomatic subjects), Sood et al. reported a prevalence of newly diagnosed CD in 1 in 310 children on a sample of 4,347 school-age children from Punjab (Sood et al., 2006). An epidemiological study in Leicestershire (United Kingdom) revealed that CD had an incidence of 6.9 and 0.9 per 10,000 individuals/year among subjects of Punjabi and Gujarati communities of Indian origin, respectively. Higher relative risk was found among the Punjabi community: it was 2.9 times higher than Europeans and 8.1 times higher than Gujaratis (Sher et al., 1993). In Indian children, CD is predominantly associated with the DQ2 allele, often in linkage disequilibrium with the A26-B8-DR3 alleles (the socalled Indian haplotype, a variant of the ancestral Caucasian haplotype A1-B8DR3-DQ2) (Kaur et al., 2002). There is a regional difference of CD occurrence that is possibly linked to genetic differences coupled with variations in differences in the staple food (wheat in north India and rice in south India). A DR3 allele frequency of 14.9% has been reported in north India (Delhi). This value is comparable to those found in south India (Tamil Nadu), which are 14.3% among Yadhavas and 11.6% among Piramalai Kallars castes. However, a major difference in DQ2 allele frequency exists between the two regions: in north India, it is 31.9%, while in south India it is 12.8% (Piramalai Kallars) and 9% (Yadhavas) (Yachha, 2006). Clinical studies usually describe typical or “hypertypical” cases, with chronic diarrhea, anemia, and stunting the commonest symptoms in children. Recently, there have been reports of atypical CD cases (18/42 celiacs) presenting with short stature, anemia, abdominal distention, rickets, constipation, diabetes mellitus, and delayed puberty.

Children with atypical CD are significantly older than classical cases (median age 10.4 years versus 5.5 years) (Sharma et al., 2006). Besides all the reported studies, the overall prevalence of CD in India is not known yet, but is likely to be high in the so-called “celiac belt,” a part of North India where wheat is a staple food (Yachha, 2006).

6 The Science of Gluten-Free Foods and Beverages

There are only anecdotal reports of CD in far eastern countries. Overall, given the low prevalence of HLA predisposing genes DQ2/DQ8 as well as the low/absent gluten consumption, reduced disease prevalence should be expected in those populations.

CD IN DEVELOPING COUNTRIES In the past, the burden of disease caused by CD in developing countries has been largely underestimated. This situation was caused by several factors, particularly 1) the common belief that CD does not exist in developing countries, 2) poor awareness of the clinical variability of CD, 3) scarcity of diagnostic facilities, and 4) more emphasis on other causes of small intestinal damage, such as intestinal tuberculosis and environmental enteropathy. It is also possible that the prevalence of CD is increasing in some developing countries because of the widespread diffusion of Western dietary habits, and thus increasing consumption of gluten-containing cereals. We recently suggested that the abrupt modification of dietary habits is one of the causes of the huge prevalence of CD among the Saharawis. Historically, the Bedouin diet was based on prolonged breastfeeding, camel milk, meat, dates, sugar, and small amounts of cereals and legumes. Over the last century, however, the Saharawi dietary habits have changed dramatically because of European colonization, and products made with wheat flour, especially bread, have become the staple food.

Clinically, the condition of the typical child with CD in a developing country resembles the picture of chronic protein-energy malnutrition known as “kwashiorkor.” Chronic diarrhea, abdominal distention, stunting (height for age lower than 2 SD), and anemia are frequent findings. Severe stunting is associated with an increased risk of mortality, especially among children with protracted diarrhea. The risks of developing severe diarrhea and dying from dehydration are greatest among the youngest children, especially during the summer.

The reliability of serological CD autoantibodies in developing countries was a matter of debate. Different studies in South America, North Africa, and India have recently shown that both the EMA and the anti-tTG antibodies are also highly specific indicators of celiac autoimmunity in subjects with a high rate of infectious or parasitic diarrhea (Yachha et al., 2006). As a matter of fact, the “weight” of these tests is even stronger than in developed countries, because a certain degree of nonspecific, celiaclike damage of the small intestinal mucosa (with increased intraepithelial lymphocyte count and reduced villous height/crypt depth ratio) is a frequent finding at the biopsy (so-called environmental enteropathy). The recent introduction of a reliable quick test for the point-of-care determination of IgA class antitTG antibodies on a drop of whole blood could overcome, at least in part, problems related to the scarcity of sophisticated diagnostic equipment (Raivio et al., 2006).

Treatment of CD is based on a lifelong dietary exclusion of gluten-containing cereals like wheat, barley, and rye. In most developed countries, this is easily accomplished by using both cereals that do not contain gluten (e.g., rice and maize) and palatable, gluten-free, commercially available products that are specifically designed for patients with CD. In contrast, treating the disease in the context of a developing country can be extremely difficult. To be effective, implementation of a gluten-free diet has to take local dietary habits into account by using naturally gluten-free products that are locally available, such as millet, manioca, and rice. How-

Catassi and Yachha 7

ever, in order to avoid cross-contamination with gluten, dedicated machinery needs to be used to mill these starchy foods. The treatment strategy should also include educational courses for doctors, nurses, dieticians, school personnel, affected families, and the general population. Finally, the implementation of patients’ groups can help affected individuals to cope with the daily difficulties of treatment and to maintain contacts with other national societies and international agencies.

CD PREVALENCE IN AT-RISK GROUPS Studies all over the world have shown that the prevalence of CD is definitely increased in specific population subgroups. The risk of CD in first-degree relatives has been reported to be 6–7% on average, mostly ranging from 3 to 10% (Fasano and Catassi, 2001). In a Finnish study on 380 CD patients and 281 patients with dermatitis herpetiformis, the mean disease prevalence was 5.5%, distributed as follows: 7% among siblings, 4.5% among parents, and 3.5% among children (Hervonen et al., 2002). Moreover, the prevalence of CD is also increased in second-degree relatives, highlighting the importance of genetic predisposition as a risk factor.

CD prevalence is increased in autoimmune diseases, especially type 1 diabetes (T1D) and thyroiditis, but also in less common disorders such as Addison’s disease or autoimmune myocarditis. The average prevalence of CD among children with T1D is 4.5% (0.97–16.4%) (Holmes, 2002). Usually T1D is diagnosed first, while CD is often subclinical and detectable only by serological screening. The increased frequency of CD in several thyroid diseases (Hashimoto’s thyroiditis, Graves’ disease, and primary hypothyroidism) is well established. A three- to fivefold increase in CD prevalence has been reported in subjects with autoimmune thyroid disease.

On the other hand, CD-associated hypothyroidism may sometimes lack features of an autoimmune process. Interestingly, treatment of CD by gluten withdrawal may lead to the normalization of subclinical hypothyroidism (Sategna-Guidetti et al., 2001). An increased frequency of CD is found in some genetic diseases, especially Down, Turner, and Williams syndromes. In a multicenter Italian study on 1,202 subjects with Down syndrome, 55 CD cases were found, with a prevalence of this disease association of 4.6% (Bonamico et al., 2001). In children with Down syndrome, CD is not detectable on the basis of clinical findings alone and is therefore underdetected. Even when there are symptoms, they may be considered clinically insignificant or possibly attributed to Down syndrome itself. Nevertheless, the reported amelioration of gastrointestinal complaints on a gluten-free diet for all symptomatic patients suggests that identification and treatment can improve the quality of life for these children.

Selective IgA deficiency (SIgAD, total serum IgA lower than 5 mg %) predisposes to CD development, and this primary immunodeficiency is 10–16 times more common in patients with CD than in the general population (Cataldo et al., 1998).

Patients with SigAD and CD are missed by using the class A anti-tTG test (or any other IgA-based test, e.g., EMA) for screening purposes. For this reason, it is appropriate to 1) check the total level of serum IgA in patients screened for CD and 2) perform an IgG-based test (e.g., IgG anti-tTG and/or IgG antigliadin) if total IgA is lower than normal.

8 The Science of Gluten-Free Foods and Beverages

THE CELIAC ICEBERG The epidemiology of CD is efficiently conceptualized by the iceberg model, which retains its validity across different populations in the world (Fasano and Catassi, 2001). The prevalence of CD can be conceived as the overall size of the iceberg, which is not only influenced by the frequency of the predisposing genotypes in the population, but also by the pattern of gluten consumption. In many countries, the prevalence of CD is roughly in the range of 0.5–1% of the general population. A sizable portion of these cases is properly diagnosed because of suggestive complaints (e.g., chronic diarrhea, unexplained iron deficiency) or other reasons (e.g., family history of CD). These cases make up the visible part of the celiac iceberg, which can be expressed in quantitative terms by the incidence of the disease. In developed countries, for each diagnosed case of CD, an average of five to 10 cases remain undiagnosed (the submerged part of the iceberg), usually because of atypical, minimal, or even absent complaints. These undiagnosed cases remain untreated and are therefore exposed to the risk of long term complications.

The level of the “water line,” namely the ratio of diagnosed to undiagnosed cases, depends mostly on the physician’s tendency to request serological CD markers in situations of low clinical suspicion, such as awareness of CD clinical polymorphism.

The best approach to the iceberg of undiagnosed CD seems to be a systemic process of case-finding focused on at-risk groups, a procedure that minimizes costs and is ethically appropriate. Increased awareness of the clinical polymorphism of CD, coupled with a low threshold for serological testing, can efficiently uncover a large portion of the submerged CD iceberg. Primary care serves as the natural setting of this selective screening. A primary care practice provides the best opportunity to first identify individuals who are at risk for CD and need referral for definitive diagnosis. We recently completed a multicenter, prospective, case-finding study using serological testing (IgA class anti-tTG antibody determination) of adults who were seeking medical attention from their primary care physician in the United States and Canada (Catassi et al., 2007). By applying simple and well-established criteria for CD case-finding on a sample of adults, we achieved a 32- to 43fold increase in the diagnostic rate of this condition. The most frequent risk factors for undiagnosed CD were a) thyroid disease, b) positive family history for CD, c) persistent gastrointestinal complaints, and d) iron deficiency with or without anemia. Many newly diagnosed cases of CD reported a longstanding history of symptoms (usually of years) that should have raised the suspicion of CD well before.

CONCLUSIONS CD is one of the most common lifelong disorders in the world (Fig. 1). In countries populated by individuals of European origin, CD affects approximately 1% of the general population. CD is also a common disease in North Africa, the Middle East, and India. The huge prevalence of CD in the Saharawi people (5.6%) is probably related to strong genetic predisposition and abrupt dietary changes. In developing countries, CD is sometimes a severe disease, characterized by chronic diarrhea, stunting, anemia, and increased mortality. Further studies are needed to quantify the incidence of the celiac condition in apparently “celiac-free” areas like Sub-Saharan Africa and the Far East. In many developing countries, the frequency

Catassi and Yachha 9

Fig. 1. Prevalence (and 95% CI) of CD in different countries. EU = European Union; USA = United States of America; SAH = Saharawi; TUR = Turkey; IRAN = Iran; MEX = Mexico; BRA = Brazil.

of CD is likely to increase in the near future, given the diffuse tendency to adopt a Western, gluten-rich dietary pattern. Because most current cases escape diagnosis in all parts of the world, an effort should be made to increase the awareness of CD polymorphism. A cost-effective case-finding policy could significantly reduce the morbidity and mortality associated with untreated disease.

LITERATURE CITED Abu-Zekry, M., Kryszak, D., Diab, M., Catassi, C., and Fasano, A. (2008). Prevalence of celiac disease in Egyptian children disputes the east-west agriculture-dependent spreading of the disease. J. Pediatr.

Gastroenterol. Nutr. In press.

Bonamico, M., Mariani, P., Danesi, H. M., Crisogianni, M., Failla, P., Gemme, G., Quartino, A. R., Giannotti, A., Castro, M., Balli, F., Lecora, M., Andria, G., Guariso, G., Gabrielli, O., Catassi, C., Lazzari, R., Balocco, N.A., De Virgiliis, S., Culasso, F., and Romano, C. (2001). Prevalence and clinical picture of celiac disease in Italian Down syndrome patients: a multicenter study. J. Pediatr.

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Cataldo, F., Marino, V., Ventura, A., Bottaro, G., and Corazza, G. (1998). Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study.

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Catassi, C., Fabiani, E., Rätsch, I. M., Coppa, G. V., Giorgi, P. L., Pierdomenico, R., Alessandrini, S., Iwanejko, G., Domenici, R., Mei, E., Miano, A., Marani, M., Bottaro, G., Spina, M., Dotti, M., Montanelli, A., Barbato, M., Viola, F., Lazzari, R., Vallini, M., Guariso, G., Plebani, M., Cataldo, F., Traverso, G., and Ventura, A. (1996). The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr. Suppl. 412:29-35.

Catassi, C., Rätsch, I. M., Gandolfi, L., Pratesi, R., Fabiani, E., El Asmar, R., Frijia, M., Bearzi, I., and Vizzoni, L. (1999). Why is coeliac disease endemic in the people of Sahara? Lancet 354:647-648.

Catassi, C., Doloretta Macis, M., Rätsch, I. M., De Virgilis, S., and Cucca, F. (2001). The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence. Tissue Antigens 58:402-406.

Catassi, C., Kryszak, D., Louis-Jacques, O., Duerksen, D. R., Hill, I., Crowe, S. E., Brown, A. R., Procaccini, N. J., Wonderly, B. A., Hartley, P., Moreci, J., Bennett, N., Horvath, K., Burk, M., and Fasano, A. (2007). Detection of celiac disease in primary care: a multicenter case-finding study in North America. Am. J. Gastroenterol. 102:1-7.

Csizmadia, C. G. D. S., Mearin, M. L., von Blomberg, B. M. E., Brand, R., and Verloove-Vanhorick, S. P. (1999). An iceberg of childhood coeliac disease in the Netherlands. Lancet 353:813-814.