Best Practice & Research Clinical Gastroenterology 29 (2015) 365e379
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Best Practice & Research Clinical Gastroenterology
1
Celiac disease from a global perspective Elena Lionetti, MD, PhD, Assistant Professor a, 1, Simona Gatti, MD, PhD b, 2, Alfredo Pulvirenti, PhD, Professor c, 3, Carlo Catassi, MD, Professor b, d, * a
Department of Paediatrics, University of Catania, Via S. Sofia 78, 95124 Catania, Italy Department of Paediatrics, Marche Polytechnic University, Ancona, Via Corridoni 11, 60123 Ancona, Italy c Department of Clinical and Molecular Biomedicine, University of Catania, Via S. Sofia 78, 95124 Catania, Italy d The Division of Paediatric Gastroenterology and Nutrition, Center for Celiac Research, MassGeneral Hospital for Children, 55 Fruit Street, Boston, MA 02114, USA b
a b s t r a c t Keywords: Coeliac disease Epidemiology Incidence Prevalence Screening
Celiac disease (CD) is one of the commonest lifelong disorders in countries populated by individuals of European origin, affecting approximately 1% of the general population. This is a common disease also in North Africa, Middle East and India. The widespread diffusion of CD is not surprising given that its causal factors (HLA predisposing genotypes and consumption of gluten-containing cereals) show a worldwide distribution. Further studies are needed to quantify the incidence of CD in apparently “celiac-free” areas such as Sub-Saharan Africa and Far East. Several reports have shown that CD is increasing in frequency in different geographic areas. Genetic factors do not explain the rising incidence during the last decades; environmental or lifestyle factors may be responsible for these changes over time. The majority of patients with CD are still undiagnosed all over the world, leading to debate about the need of screening program. © 2015 Elsevier Ltd. All rights reserved.
Politecnica delle Marche, Via F Corridoni 11, 60123 Ancona, * Corresponding author. Department of Pediatrics, Universita Italy. Tel.: þ39 071 5962364; fax: þ39 071 36281. E-mail addresses: [email protected] (E. Lionetti), [email protected] (S. Gatti), [email protected] (A. Pulvirenti), [email protected] (C. Catassi). 1 Tel.: þ39 095 3781782; fax: þ39 095 3781288. 2 Tel.: þ39 071 5962364; fax: þ39 071 36281. 3 Tel.: þ39 095 738 3087; fax: þ39 095 330094. http://dx.doi.org/10.1016/j.bpg.2015.05.004 1521-6918/© 2015 Elsevier Ltd. All rights reserved.
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Introduction Celiac disease (CD) is a systemic immune-mediated disorder caused by the ingestion of glutencontaining grains in genetically susceptible persons [1]. In the past, it was considered a rare disorder, mostly affecting individuals of European origin, and usually characterized by onset during the first years of life. Earlier investigations measured the incidence of CD, namely the number of “new” diagnoses in the study population during a certain period. One of the oldest epidemiologic studies on CD conducted in 1950 established that the cumulative incidence of the disease in England and Wales was 1/8000, whereas an incidence of 1/4000 was detected in Scotland [2]. The diagnosis at that time was entirely based on the detection of typical gastrointestinal symptoms. The awareness of the disease greatly increased in the 1960s when more specific tests for malabsorption and the paediatric peroral biopsy technique became available [3]. Consequently, an elevated incidence of the disease (which in the middle 1970s reached peaks of 1/450) was reported in studies from Ireland [4], Scotland [5], and Switzerland [6]. The availability of highly sensitive and specific serological tools, first the anti-gliadin (AGA) and later the anti-endomysium (EMA) and the anti-transglutaminase (tTG) antibodies, made it possible to evaluate the true prevalence of CD (number of affected persons in a population at a given time), showing an unsuspected frequency of clinically atypical or even silent forms of CD. Approximately twenty years ago Italy was the birth land of the new “era” of CD epidemiology, the one based on serological screening of general population samples. On a sample of 17,201 healthy Italian students it was shown that CD is much more common than previously thought and that most atypical cases remained undiagnosed unless actively searched by serological screening. The overall prevalence of CD (including known CD cases) was 1 in 184 subjects. The ratio of known (previously diagnosed) to undiagnosed CD cases was as high as 1e7 [7]. Using these sensitive serological tools for screening purposes, a huge number of further studies have shown that CD is one of the commonest, lifelong disorders affecting mankind all over the world, with a mean prevalence estimate of 0.9% [8]. Worldwide distribution of HLA and wheat consumption: the “evolutionary paradox of CD” The widespread diffusion of CD is not surprising at all, given that its causal factors, HLApredisposing-genotypes (DQ2 and DQ8) and consumption of gluten-containing cereals, show a worldwide distribution. We recently reviewed data on worldwide prevalence of CD, wheat consumption, and frequencies of HLA-DQ2 and HLA-DQ8 haplotypes and combined the three geographical maps to investigate their mutual relationship [8]. The global level of wheat consumption ranged between 21 and 564 g/person/day (Fig. 1); frequencies of HLA-DQ2 and HLA-DQ8 ranged between 0 and 28% and between 1 and 9%, respectively (Figs. 2 and 3). Interestingly, a significant correlation between the level of wheat consumption and the frequency of HLA-DQ2 or the sum of DQ2 and DQ8 was found worldwide (Fig. 4) [8]. Wheat consumption and HLA-DQ2 tended, indeed, to co-localize in different continents; in India wheat consumption is higher in Northern-Western states such as Punjab, Haryana, Delhi, Rajasthan, Uttar Pradesh, Bihar and Madhya Pradesh (so-called “celiac belt”). Likewise, the DQ2 allele frequency is higher in North (31.9%) than in South India (12.8% for Piramalai Kallars and 9% for Yadavas) [9]. In Africa the frequency of HLA-DQ2 is higher in the Northern populations consuming a gluten-rich diet, such as Saharawi (39%) [10], Libya (34%) [11], Algeria (28.3%) [12], Tunisia (23.4%) [12], Maroc (25%) [12], than sub-Saharan populations showing low frequency of DQ2 (Rwanda 15.5%, Tanzania 13.5%, Cameroon 7%) [12] and low level of wheat consumption [8]. We also observed a significant correlation between the frequency of HLA-DQ2 and the duration of wheat consumption according to the pattern of wheat culture spreading [8]. The history of CD is indeed related to the spreading of wheat cultivation after the agricultural revolution. Domestication of glutencontaining cereals began approximately 10,000 years ago in Neolithic settlements in the north-eastern (Turkey, Iran, and Iraq) and in the south-western (Palestine, Syria, and Lebanon) regions of the socalled Fertile Crescent area. Cultivation of wheat and barley slowly spread north-westward across Europe to reach Western countries, like Britain, “only” 4000 years ago [13]. The agricultural revolution paved the way to new diseases, such as CD. Since treatment with the GFD was not available in the
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Fig. 1. World map of level of wheat consumption (g/person/day). Data from the Food and Agriculture Organization of the United Nations database (http://www.fao.org).
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Fig. 2. World map of frequency of HLA-DQ2 (%). Data from the allelefrequencies.net database [12].
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Fig. 3. World map of frequency of HLA-DQ8 (%). Data from the allelefrequencies.net database [12].
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Fig. 4. Correlation between the level of wheat consumption and the frequency of HLA-DQ2 [8].
ancient time, the CD geno-/phenotype could have exerted a negative impact on human reproductive fitness and survival. As a consequence of a prolonged negative selective pressure, CD and the genotypes predisposing to it should be less common in the Middle East than in European countries (as originally theorized by Simoons [14]). On the contrary, we found that CD is equally common in the UK and Turkey, and the frequency of HLA-DQ2 is even higher in Turkey and Iran, (countries consuming more wheat and for a longer duration of time) than Finland and Ireland (countries consuming less gluten and for a shorter duration of time) [8]. Therefore, despite its negative effects on human health, the CD phenotype has not disappeared over time, but is even increasing in areas with high density of both gluten consumption and HLA-genotypes, the so-called “evolutionary paradox of CD” [15,16]. To explain this paradoxical distribution of the two CD-causative factors we hypothesized different mechanisms: (a) a founder effect related to the demic diffusion of Middle East farmers into Europe; (b) positive selection of the major CD-predisposing haplotype, that is HLA-DQ2. The driver of HLA-DQ2 selection could have been protection against dental caries, a disease that certainly had a tremendous impact on the health and reproductive fitness of ancient populations [8]. Thus, the highest prevalence of DQ2 among wheat-consuming populations could be another example of evolutionary adaptation driven by the dietary changes imposed by the agricultural revolution, in analogy to lactase persistence in milk-drinking populations and glucose-6-phosphate deficiency in Mediterranean populations consuming broad beans. In this perspective, CD could simply represent the effect of a genetic structure (DQ2 positivity) that in the past conferred resistance to a negative consequence of a wheatbased diet [8]. CD in western world Several studies evaluated the prevalence of CD in the general population [11,17e51]. The geoepidemiology of CD all over the world is shown in Fig. 5. CD prevalence in Europe In Europe a recently published large international, multicentre study investigated a wide population sample in four different countries: on average, the overall prevalence of CD was 1%, with large variations between countries (2.0% in Finland, 1.2% in Italy, 0.9% in Northern Ireland, and 0.3% in Germany) [24]. Although these countries have similar wheat consumption levels and comparable HLA
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Fig. 5. World map of celiac disease prevalence (%). Data from studies based on the screening of unselected samples [11,17e48]. Studies on blood donors were excluded because they differed from the general population in social, health-related, and gender variables.
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haplotype frequencies, the prevalence of CD differs, suggesting that other environmental and/or genetic factors can significantly impact disease outcome [8]. CD prevalence in America and Oceania Similar rates have been reported for the US population (0.7%) [48], and for developed countries populated by individuals of European origin, e.g., Australia (0.4%) [19] and New Zealand (1.1%) [35]. The presence of CD is long established also in many South American countries that are mostly populated by individuals of European origin. Among Brazilian blood donors, the prevalence of CD ranged between 1:681 [49] and 1:214 [50]. It is worth noting that studies on blood donors tend to underestimate the prevalence of CD, as these individuals represent the “healthiest” segment of the population and are mostly males (while CD is more common among women). Among Brazilian school children the prevalence of CD was 0.5% [20]. In Argentina, Gomez et al found an overall prevalence of 1 on 167 on 2000 adults involved in a prenuptial examination [18]. Increasing prevalence of CD In Western countries the overall prevalence of CD is on the rise. A 6.4-fold increase in incidence has been recently described in Scotland from 1990 to 2009 and particularly classical cases of CD are increasing, indicating a true rise in the incidence of paediatric CD [52]. A recent US study showed that CD prevalence was only 0.2% in the year 1975, and increased five-fold during the following 25 years [53]. It should be noted that all available studies on CD prevalence around the world are not up-to-date [11,17e51]; given the observed raised in frequency of the disease, it's time for new screening studies to be performed in different areas of the world for epidemiological purposes aiming to give an updated picture of the CD distribution. The reasons for the reported raise in prevalence are unclear, but have to do with the environmental components of CD (changes in the quantity and quality of ingested gluten, infant feeding patterns, the spectrum of intestinal infections, gut microbiota colonization, etc.). Variation in the pattern of infant nutrition could influence the prevalence of CD at the population level, as suggested by the analysis of an epidemic of early-onset CD observed in Sweden during the 1980e1990s. The Swedish data indicated that the disease risk was substantially lower in infants introducing small amount of gluten when still breast-fed [54]. The protective role of breastfeeding has been supported by other observational, retrospective studies and summarized in a meta-analysis [55]. As far as weaning, an increased risk of CD has been reported in infants introducing gluten-containing food either before the age of 4 months or after 6 months, supporting the view of the “window” period of facilitated tolerance (4e6 months) [56]. These observations have recently been challenged by a large epidemiological survey performed in Norway [57]. The major results of this study were somewhat shocking: (a) breast-feeding did not exert any protection against development of CD. Instead, mean duration of breastfeeding had been significantly longer in CD children (10.4 months) than controls (9.9 months) and the disease risk was significantly higher in infants breast-fed for more than 12 months; (b) gluten introduction under continued breast-feeding was not protective; (c) in the adjusted analysis, only delayed (>6 months) but not early (1.3 billion people, China is the most populous nation and the second largest by land area in the world. Both CD-causing factors e gluten consumption (particularly in the northern part of the country) and HLA-predisposing genotypes (with a lower prevalence than in Western countries) e are largely diffused in China. In the current literature a total of 18 cases of biopsy proven CD were described in Chinese patients [79]. Epidemiological studies are needed to quantify the impact of this condition in this country. Finally, CD is likely to be rare in Japan, Indonesia, Korea, the Philippines and many smaller Pacific islands because of low wheat consumption and a low frequency of HLA-DQ2.
Under-recognition of CD CD is not recognized in many developing countries, and even in nations where CD is recognized only the most symptomatic patients are being diagnosed. The foremost among the possible explanations for under-diagnosis of CD is (1) the mistaken belief that CD is rare/uncommon in this part of the world; (2) poor awareness of the clinical variability of CD; (3) scarcity of diagnostic facilities; (4) more emphasis on other causes of small intestinal damage, such as intestinal tuberculosis and environmental enteropathy [13,80,81]. It is also possible that the prevalence of CD is increasing in some developing countries because of the widespread diffusion of Western dietary habits, with increasing consumption of gluten-containing cereals. We 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 and meat, dates, sugar, and small amounts of cereals and legumes. Over the last century, however, the Saharawi dietary habits have changed dramatically because of the
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European colonization, and products made with wheat flour, especially bread, have become the staple food [80]. Gluten free-diet in developing world Prescribing GFD is easy, but its institution and maintenance of adherence pose the real challenges, therefore treating the disease in the context of a developing country can be extremely difficult. At present, there is neither an organized sector nor industry for gluten-free products in developing countries, and gluten-free food products are not readily available. Gluten is ubiquitous in the food industry and often used in a variety of food items. More importantly, there is no gluten labelling in the available food products. The patient cannot judge the safety of an over-the-counter food product. To be effective, the institution of a GFD has to take local dietary habits into account, e.g. by using naturally gluten-free products that are locally available, such as millet, manioc and rice. However, in order to avoid cross-contamination with gluten, dedicated machinery needs to be used to mill these starchy foods. There is an urgent need for legislation to enforce gluten labelling of the marketed food products. 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 [80,81]. Summary Available data suggest that (a) CD is one of the commonest, lifelong disorders affecting mankind all over the world, including many developing areas, with a mean prevalence of 0.9% worldwide, and (b) its prevalence is truly increasing. The widespread diffusion of CD is not surprising given that its causal factors (HLA-predisposing-genotypes and consumption of gluten-containing cereals) show a worldwide distribution. The available studies on CD prevalence are not up-to-date. New epidemiological studies aimed at evaluating the up-dated worldwide CD distribution, the role of environmental factors in CD development and to measure the prevalence of CD as well as the relevant parameters (level of gluten intake, frequency and pattern of CD-predisposing genotypes) in new geographic areas will play an instrumental role for increasing the awareness of CD and, consequently, the detection rate of this chameleonic disorder. These studies will also be instrumental to explain the dynamics of geneenvironmental interactions driving the current CD epidemic worldwide. As most cases currently escape diagnosis all over the world, an effort should be done to increase the awareness of CD complexicty with regard to the associated symptoms. To improving the diagnostic rate, the debate on mass screening versus case finding is still open. Well-performed prospective studies on long-term benefits of serological screening in asymptomatic populations are needed in the context of decision policies on CD screening program.
Practice points CD is one of the commonest, lifelong disorders affecting mankind all over the world. Its prevalence is truly increasing; the environmental components of CD (changes in the quantity and quality of ingested gluten, infant feeding patterns, the spectrum of intestinal infections, gut microbiota colonization, etc.) may be responsible for this change over time. The timing of gluten-introduction in high-risk children and the duration of breast-feeding do not appear to influence the development of CD in childhood. Other environmental factors need to explored. The majority of patients with CD are still undiagnosed all over the world. The debate on mass screening versus case finding is still open.
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Research agenda Available studies on CD prevalence all over the world are not up-to-date; new epidemiological studies aiming at evaluating the current worldwide CD prevalence will give an updated picture of CD distribution. Further studies are needed to quantify the incidence of CD in apparently “celiac-free” areas like Sub-Saharan Africa and Far East to increase the awareness of CD and the detection rate of this disorder. Future direction of research should be focused on the role of environmental factors in CD development and the dynamics of gene-environmental interactions driving the current CD epidemic worldwide. Well-performed prospective studies on long-term benefits of serological screening in asymptomatic populations are needed in the context of decision policies on CD screening program.
Conflict of interest statement Carlo Catassi served as consultant for Menarini diagnostics s.r.l., for Dr Shaer, and for Heinz Company. Elena Lionetti served as consultant for Heinz Company.
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New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. Int Rev Immunol 2011;30:219e31. *[61] Catassi C, Gatti S, Fasano A. The new epidemiology of celiac disease. J Pediatr Gastroenterol Nutr 2014;59(Suppl. 1):S7e9. *[62] Catassi C, Fasano A. Coeliac disease. The debate on coeliac disease screening e are we there yet? Nat Rev Gastroenterol Hepatol 2014;11:457e8. n P, Stene LC. Epidemiology of coeliac disease and comorbidity in Norwegian children. J Pediatr [63] Størdal K, Bakken IJ, Sure Gastroenterol Nutr 2013;57:467e71. A, Carroccio A, et al. Non-celiac gluten sensitivity: the new frontier of gluten[64] Catassi C, Bai JC, Bonaz B, Bouma G, Calabro related disorders. Nutrients 2013;5:3839e53. €nen H, Laurila K, Huhtala H, et al. Benefits of a gluten-free diet for asymptomatic [65] Kurppa K, Paavola A, Collin P, Sieva patients with serologic markers of celiac disease. Gastroenterology 2014;147:610e7. n A, Emmelin M, Carlsson A, Hammarroth S, Karlsson E, Ivarsson A. Mass screening for celiac disease from the [66] Rose perspective of newly diagnosed adolescents and their parents: a mixed-method study. BMC Public Health 2011;11:822. € C, Hulte n S, Midhagen G, Stro €m M, Svensson H, et al. Living with coeliac disease: controlled study of the [67] Hallert C, Gr€ anno burden of illness. Scand J Gastroenterol 2002;37:39e42. *[68] Health Quality Ontario. Clinical utility of serologic testing for celiac disease in asymptomatic patients: an evidence-based analysis. Ont Health Technol Assess Ser 2011;11:1e63. [69] Mearin ML, Catassi C, Brousse N, Brand R, Collin P, Fabiani E, et al. European multi-centre study on coeliac disease and non-Hodgkin lymphoma. Eur J Gastroenterol Hepatol 2006;18:187e94. [70] Lohi S, Maki M, Montonen J, Knekt P, Pukkala E, Reunanen A, et al. 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Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
1
Celiac disease from a global perspective Elena Lionetti, MD, PhD, Assistant Professor a, 1, Simona Gatti, MD, PhD b, 2, Alfredo Pulvirenti, PhD, Professor c, 3, Carlo Catassi, MD, Professor b, d, * a
Department of Paediatrics, University of Catania, Via S. Sofia 78, 95124 Catania, Italy Department of Paediatrics, Marche Polytechnic University, Ancona, Via Corridoni 11, 60123 Ancona, Italy c Department of Clinical and Molecular Biomedicine, University of Catania, Via S. Sofia 78, 95124 Catania, Italy d The Division of Paediatric Gastroenterology and Nutrition, Center for Celiac Research, MassGeneral Hospital for Children, 55 Fruit Street, Boston, MA 02114, USA b
a b s t r a c t Keywords: Coeliac disease Epidemiology Incidence Prevalence Screening
Celiac disease (CD) is one of the commonest lifelong disorders in countries populated by individuals of European origin, affecting approximately 1% of the general population. This is a common disease also in North Africa, Middle East and India. The widespread diffusion of CD is not surprising given that its causal factors (HLA predisposing genotypes and consumption of gluten-containing cereals) show a worldwide distribution. Further studies are needed to quantify the incidence of CD in apparently “celiac-free” areas such as Sub-Saharan Africa and Far East. Several reports have shown that CD is increasing in frequency in different geographic areas. Genetic factors do not explain the rising incidence during the last decades; environmental or lifestyle factors may be responsible for these changes over time. The majority of patients with CD are still undiagnosed all over the world, leading to debate about the need of screening program. © 2015 Elsevier Ltd. All rights reserved.
Politecnica delle Marche, Via F Corridoni 11, 60123 Ancona, * Corresponding author. Department of Pediatrics, Universita Italy. Tel.: þ39 071 5962364; fax: þ39 071 36281. E-mail addresses: [email protected] (E. Lionetti), [email protected] (S. Gatti), [email protected] (A. Pulvirenti), [email protected] (C. Catassi). 1 Tel.: þ39 095 3781782; fax: þ39 095 3781288. 2 Tel.: þ39 071 5962364; fax: þ39 071 36281. 3 Tel.: þ39 095 738 3087; fax: þ39 095 330094. http://dx.doi.org/10.1016/j.bpg.2015.05.004 1521-6918/© 2015 Elsevier Ltd. All rights reserved.
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Introduction Celiac disease (CD) is a systemic immune-mediated disorder caused by the ingestion of glutencontaining grains in genetically susceptible persons [1]. In the past, it was considered a rare disorder, mostly affecting individuals of European origin, and usually characterized by onset during the first years of life. Earlier investigations measured the incidence of CD, namely the number of “new” diagnoses in the study population during a certain period. One of the oldest epidemiologic studies on CD conducted in 1950 established that the cumulative incidence of the disease in England and Wales was 1/8000, whereas an incidence of 1/4000 was detected in Scotland [2]. The diagnosis at that time was entirely based on the detection of typical gastrointestinal symptoms. The awareness of the disease greatly increased in the 1960s when more specific tests for malabsorption and the paediatric peroral biopsy technique became available [3]. Consequently, an elevated incidence of the disease (which in the middle 1970s reached peaks of 1/450) was reported in studies from Ireland [4], Scotland [5], and Switzerland [6]. The availability of highly sensitive and specific serological tools, first the anti-gliadin (AGA) and later the anti-endomysium (EMA) and the anti-transglutaminase (tTG) antibodies, made it possible to evaluate the true prevalence of CD (number of affected persons in a population at a given time), showing an unsuspected frequency of clinically atypical or even silent forms of CD. Approximately twenty years ago Italy was the birth land of the new “era” of CD epidemiology, the one based on serological screening of general population samples. On a sample of 17,201 healthy Italian students it was shown that CD is much more common than previously thought and that most atypical cases remained undiagnosed unless actively searched by serological screening. The overall prevalence of CD (including known CD cases) was 1 in 184 subjects. The ratio of known (previously diagnosed) to undiagnosed CD cases was as high as 1e7 [7]. Using these sensitive serological tools for screening purposes, a huge number of further studies have shown that CD is one of the commonest, lifelong disorders affecting mankind all over the world, with a mean prevalence estimate of 0.9% [8]. Worldwide distribution of HLA and wheat consumption: the “evolutionary paradox of CD” The widespread diffusion of CD is not surprising at all, given that its causal factors, HLApredisposing-genotypes (DQ2 and DQ8) and consumption of gluten-containing cereals, show a worldwide distribution. We recently reviewed data on worldwide prevalence of CD, wheat consumption, and frequencies of HLA-DQ2 and HLA-DQ8 haplotypes and combined the three geographical maps to investigate their mutual relationship [8]. The global level of wheat consumption ranged between 21 and 564 g/person/day (Fig. 1); frequencies of HLA-DQ2 and HLA-DQ8 ranged between 0 and 28% and between 1 and 9%, respectively (Figs. 2 and 3). Interestingly, a significant correlation between the level of wheat consumption and the frequency of HLA-DQ2 or the sum of DQ2 and DQ8 was found worldwide (Fig. 4) [8]. Wheat consumption and HLA-DQ2 tended, indeed, to co-localize in different continents; in India wheat consumption is higher in Northern-Western states such as Punjab, Haryana, Delhi, Rajasthan, Uttar Pradesh, Bihar and Madhya Pradesh (so-called “celiac belt”). Likewise, the DQ2 allele frequency is higher in North (31.9%) than in South India (12.8% for Piramalai Kallars and 9% for Yadavas) [9]. In Africa the frequency of HLA-DQ2 is higher in the Northern populations consuming a gluten-rich diet, such as Saharawi (39%) [10], Libya (34%) [11], Algeria (28.3%) [12], Tunisia (23.4%) [12], Maroc (25%) [12], than sub-Saharan populations showing low frequency of DQ2 (Rwanda 15.5%, Tanzania 13.5%, Cameroon 7%) [12] and low level of wheat consumption [8]. We also observed a significant correlation between the frequency of HLA-DQ2 and the duration of wheat consumption according to the pattern of wheat culture spreading [8]. The history of CD is indeed related to the spreading of wheat cultivation after the agricultural revolution. Domestication of glutencontaining cereals began approximately 10,000 years ago in Neolithic settlements in the north-eastern (Turkey, Iran, and Iraq) and in the south-western (Palestine, Syria, and Lebanon) regions of the socalled Fertile Crescent area. Cultivation of wheat and barley slowly spread north-westward across Europe to reach Western countries, like Britain, “only” 4000 years ago [13]. The agricultural revolution paved the way to new diseases, such as CD. Since treatment with the GFD was not available in the
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Fig. 1. World map of level of wheat consumption (g/person/day). Data from the Food and Agriculture Organization of the United Nations database (http://www.fao.org).
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Fig. 2. World map of frequency of HLA-DQ2 (%). Data from the allelefrequencies.net database [12].
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Fig. 3. World map of frequency of HLA-DQ8 (%). Data from the allelefrequencies.net database [12].
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Fig. 4. Correlation between the level of wheat consumption and the frequency of HLA-DQ2 [8].
ancient time, the CD geno-/phenotype could have exerted a negative impact on human reproductive fitness and survival. As a consequence of a prolonged negative selective pressure, CD and the genotypes predisposing to it should be less common in the Middle East than in European countries (as originally theorized by Simoons [14]). On the contrary, we found that CD is equally common in the UK and Turkey, and the frequency of HLA-DQ2 is even higher in Turkey and Iran, (countries consuming more wheat and for a longer duration of time) than Finland and Ireland (countries consuming less gluten and for a shorter duration of time) [8]. Therefore, despite its negative effects on human health, the CD phenotype has not disappeared over time, but is even increasing in areas with high density of both gluten consumption and HLA-genotypes, the so-called “evolutionary paradox of CD” [15,16]. To explain this paradoxical distribution of the two CD-causative factors we hypothesized different mechanisms: (a) a founder effect related to the demic diffusion of Middle East farmers into Europe; (b) positive selection of the major CD-predisposing haplotype, that is HLA-DQ2. The driver of HLA-DQ2 selection could have been protection against dental caries, a disease that certainly had a tremendous impact on the health and reproductive fitness of ancient populations [8]. Thus, the highest prevalence of DQ2 among wheat-consuming populations could be another example of evolutionary adaptation driven by the dietary changes imposed by the agricultural revolution, in analogy to lactase persistence in milk-drinking populations and glucose-6-phosphate deficiency in Mediterranean populations consuming broad beans. In this perspective, CD could simply represent the effect of a genetic structure (DQ2 positivity) that in the past conferred resistance to a negative consequence of a wheatbased diet [8]. CD in western world Several studies evaluated the prevalence of CD in the general population [11,17e51]. The geoepidemiology of CD all over the world is shown in Fig. 5. CD prevalence in Europe In Europe a recently published large international, multicentre study investigated a wide population sample in four different countries: on average, the overall prevalence of CD was 1%, with large variations between countries (2.0% in Finland, 1.2% in Italy, 0.9% in Northern Ireland, and 0.3% in Germany) [24]. Although these countries have similar wheat consumption levels and comparable HLA
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Fig. 5. World map of celiac disease prevalence (%). Data from studies based on the screening of unselected samples [11,17e48]. Studies on blood donors were excluded because they differed from the general population in social, health-related, and gender variables.
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haplotype frequencies, the prevalence of CD differs, suggesting that other environmental and/or genetic factors can significantly impact disease outcome [8]. CD prevalence in America and Oceania Similar rates have been reported for the US population (0.7%) [48], and for developed countries populated by individuals of European origin, e.g., Australia (0.4%) [19] and New Zealand (1.1%) [35]. The presence of CD is long established also in many South American countries that are mostly populated by individuals of European origin. Among Brazilian blood donors, the prevalence of CD ranged between 1:681 [49] and 1:214 [50]. It is worth noting that studies on blood donors tend to underestimate the prevalence of CD, as these individuals represent the “healthiest” segment of the population and are mostly males (while CD is more common among women). Among Brazilian school children the prevalence of CD was 0.5% [20]. In Argentina, Gomez et al found an overall prevalence of 1 on 167 on 2000 adults involved in a prenuptial examination [18]. Increasing prevalence of CD In Western countries the overall prevalence of CD is on the rise. A 6.4-fold increase in incidence has been recently described in Scotland from 1990 to 2009 and particularly classical cases of CD are increasing, indicating a true rise in the incidence of paediatric CD [52]. A recent US study showed that CD prevalence was only 0.2% in the year 1975, and increased five-fold during the following 25 years [53]. It should be noted that all available studies on CD prevalence around the world are not up-to-date [11,17e51]; given the observed raised in frequency of the disease, it's time for new screening studies to be performed in different areas of the world for epidemiological purposes aiming to give an updated picture of the CD distribution. The reasons for the reported raise in prevalence are unclear, but have to do with the environmental components of CD (changes in the quantity and quality of ingested gluten, infant feeding patterns, the spectrum of intestinal infections, gut microbiota colonization, etc.). Variation in the pattern of infant nutrition could influence the prevalence of CD at the population level, as suggested by the analysis of an epidemic of early-onset CD observed in Sweden during the 1980e1990s. The Swedish data indicated that the disease risk was substantially lower in infants introducing small amount of gluten when still breast-fed [54]. The protective role of breastfeeding has been supported by other observational, retrospective studies and summarized in a meta-analysis [55]. As far as weaning, an increased risk of CD has been reported in infants introducing gluten-containing food either before the age of 4 months or after 6 months, supporting the view of the “window” period of facilitated tolerance (4e6 months) [56]. These observations have recently been challenged by a large epidemiological survey performed in Norway [57]. The major results of this study were somewhat shocking: (a) breast-feeding did not exert any protection against development of CD. Instead, mean duration of breastfeeding had been significantly longer in CD children (10.4 months) than controls (9.9 months) and the disease risk was significantly higher in infants breast-fed for more than 12 months; (b) gluten introduction under continued breast-feeding was not protective; (c) in the adjusted analysis, only delayed (>6 months) but not early (1.3 billion people, China is the most populous nation and the second largest by land area in the world. Both CD-causing factors e gluten consumption (particularly in the northern part of the country) and HLA-predisposing genotypes (with a lower prevalence than in Western countries) e are largely diffused in China. In the current literature a total of 18 cases of biopsy proven CD were described in Chinese patients [79]. Epidemiological studies are needed to quantify the impact of this condition in this country. Finally, CD is likely to be rare in Japan, Indonesia, Korea, the Philippines and many smaller Pacific islands because of low wheat consumption and a low frequency of HLA-DQ2.
Under-recognition of CD CD is not recognized in many developing countries, and even in nations where CD is recognized only the most symptomatic patients are being diagnosed. The foremost among the possible explanations for under-diagnosis of CD is (1) the mistaken belief that CD is rare/uncommon in this part of the world; (2) poor awareness of the clinical variability of CD; (3) scarcity of diagnostic facilities; (4) more emphasis on other causes of small intestinal damage, such as intestinal tuberculosis and environmental enteropathy [13,80,81]. It is also possible that the prevalence of CD is increasing in some developing countries because of the widespread diffusion of Western dietary habits, with increasing consumption of gluten-containing cereals. We 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 and meat, dates, sugar, and small amounts of cereals and legumes. Over the last century, however, the Saharawi dietary habits have changed dramatically because of the
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European colonization, and products made with wheat flour, especially bread, have become the staple food [80]. Gluten free-diet in developing world Prescribing GFD is easy, but its institution and maintenance of adherence pose the real challenges, therefore treating the disease in the context of a developing country can be extremely difficult. At present, there is neither an organized sector nor industry for gluten-free products in developing countries, and gluten-free food products are not readily available. Gluten is ubiquitous in the food industry and often used in a variety of food items. More importantly, there is no gluten labelling in the available food products. The patient cannot judge the safety of an over-the-counter food product. To be effective, the institution of a GFD has to take local dietary habits into account, e.g. by using naturally gluten-free products that are locally available, such as millet, manioc and rice. However, in order to avoid cross-contamination with gluten, dedicated machinery needs to be used to mill these starchy foods. There is an urgent need for legislation to enforce gluten labelling of the marketed food products. 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 [80,81]. Summary Available data suggest that (a) CD is one of the commonest, lifelong disorders affecting mankind all over the world, including many developing areas, with a mean prevalence of 0.9% worldwide, and (b) its prevalence is truly increasing. The widespread diffusion of CD is not surprising given that its causal factors (HLA-predisposing-genotypes and consumption of gluten-containing cereals) show a worldwide distribution. The available studies on CD prevalence are not up-to-date. New epidemiological studies aimed at evaluating the up-dated worldwide CD distribution, the role of environmental factors in CD development and to measure the prevalence of CD as well as the relevant parameters (level of gluten intake, frequency and pattern of CD-predisposing genotypes) in new geographic areas will play an instrumental role for increasing the awareness of CD and, consequently, the detection rate of this chameleonic disorder. These studies will also be instrumental to explain the dynamics of geneenvironmental interactions driving the current CD epidemic worldwide. As most cases currently escape diagnosis all over the world, an effort should be done to increase the awareness of CD complexicty with regard to the associated symptoms. To improving the diagnostic rate, the debate on mass screening versus case finding is still open. Well-performed prospective studies on long-term benefits of serological screening in asymptomatic populations are needed in the context of decision policies on CD screening program.
Practice points CD is one of the commonest, lifelong disorders affecting mankind all over the world. Its prevalence is truly increasing; the environmental components of CD (changes in the quantity and quality of ingested gluten, infant feeding patterns, the spectrum of intestinal infections, gut microbiota colonization, etc.) may be responsible for this change over time. The timing of gluten-introduction in high-risk children and the duration of breast-feeding do not appear to influence the development of CD in childhood. Other environmental factors need to explored. The majority of patients with CD are still undiagnosed all over the world. The debate on mass screening versus case finding is still open.
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Research agenda Available studies on CD prevalence all over the world are not up-to-date; new epidemiological studies aiming at evaluating the current worldwide CD prevalence will give an updated picture of CD distribution. Further studies are needed to quantify the incidence of CD in apparently “celiac-free” areas like Sub-Saharan Africa and Far East to increase the awareness of CD and the detection rate of this disorder. Future direction of research should be focused on the role of environmental factors in CD development and the dynamics of gene-environmental interactions driving the current CD epidemic worldwide. Well-performed prospective studies on long-term benefits of serological screening in asymptomatic populations are needed in the context of decision policies on CD screening program.
Conflict of interest statement Carlo Catassi served as consultant for Menarini diagnostics s.r.l., for Dr Shaer, and for Heinz Company. Elena Lionetti served as consultant for Heinz Company.
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