Pediatric and Adult Celiac Disease: A Clinically Oriented Perspective

Pediatric and Adult Coeliac Disease: A Clinically Oriented Perspective provides an up-to-date, comprehensive, and critical overview of coeliac disease, its complications, and related disorders. The book covers the epidemiological, pathogenetic, diagnostic, and treatment issues including pediatric and adult cases, with a broad and international view.

This is the perfect reference for researchers dedicated to advancing the field of translational coeliac disease research as well as clinicians who are diagnosing and managing coeliac disease throughout all of its various stages.

• Provides a comprehensive and practical view, encompassing all disease forms and stages
• Covers the clinical aspects of coeliac disease at all stages, providing deep clinical insights
• Presents decision trees, tables, figures, and algorithms that aid in easily finding content to guide diagnosis

• Language: English
• Publisher: Academic Press
• Release date: Feb 28, 2024
• ISBN: 9780443133589

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Preface

Gino Roberto Corazza, Riccardo Troncone, Marco Vincenzo Lenti and Marco Silano

For many years, Italian medicine has held a prominent position in the study of celiac disease in both children and adults. Italy has hosted important international symposia, and many Italian scientists have been involved in international consensus groups and guideline development. The amount of scientific research produced in Italy competes with that of the most productive countries. Hence, it is not surprising that this book was conceived and written entirely by Italian authors, including a few who hold prestigious positions in North American institutions.

To note, this book does not aim to provide an Italian view on celiac disease, simply because such a view does not exist. The authors belong to independent groups and have gained their expertise at different foreign institutions. As a proof, throughout the book, some controversial opinions on specific topics emerge, as underlined by the editors themselves with appropriate callouts, highlighting controversial areas that may be the object of future research.

The main goals of this book are twofold. First, we wanted to provide a clear and up-to-date understanding of childhood and adult celiac disease, useful for all professionals and scientists (e.g., pediatricians, gastroenterologists, internists, pathologists, immunologists and basic scientists, dermatologists, nutritionists, and dieticians) involved in its management. Second, we aimed at having a clinical perspective as a leitmotif, as indicated in the book subtitle. However, this did not deter us from deepening those subtle mechanisms that represent the bases of the disease, since their understanding undoubtedly improves clinical practice. Furthermore, exploring the modalities of presentation of a food antigen known in its molecular structure to the immune system, the enzymatic mechanisms underlying the strengthening of its immunogenicity, the ways of clustering across autoimmune diseases, and the progression from chronic inflammation to lymphoma have made celiac disease a model of paramount importance for understanding broader mechanisms involved in the breakdown of immunological tolerance.

Going back to the clinical ground, although the spectrum of clinical presentation is wider and clearer than in the past, this disease never ceases to amaze us. The vast majority of patients are still undiagnosed, or are diagnosed with years of delay, despite the better disease awareness and the availability of accurate diagnostic tools. Recent data suggest that this happens not only in the primary care but also in the secondary care. Also, due to their relevant role in promoting educational and awareness campaigns, in fundraising for research, in supporting patients and their families, and in dealing with stakeholders and socio-political institutions, we have included a chapter dedicated to the activity of the patient association Associazione Italiana Celiachia (AIC), member of the AOECS.

We think that there is a real need for a new book because, compared to the latest on this topic, a number of novel issues and data have emerged. We will discuss the epidemiology of this constantly increasing condition, along with the many uncertainties around its differentiation from a series of emergent disorders (e.g., nonceliac gluten/wheat sensitivity, olmesartan enteropathy, immunodeficiencies, seronegative celiac disease, wheat allergy) that are yet unclear to many physicians. Furthermore, new guidelines on pediatric celiac disease were published in 2020 and the appropriateness of a biopsy-free approach in adults is still disputed. Finally, we report here for the first time a critical reappraisal of nondietary treatments, as well as the results of the recent phase II–IV trials focusing on refractory celiac disease and enteropathy-associated T-cell lymphoma.

To conclude, the editors would like to express their deepest gratitude to Tracy Tufaga, Stacy Masucci, and all the Elsevier editorial staff for their valuable assistance.

Chapter 1

The dynamic epidemiology of celiac disease

Giulia Catassi¹, Elena Lionetti², Simona Gatti² and Carlo Catassi²,    ¹Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome—Umberto I Hospital, Rome, Italy,    ²Department of Pediatrics, Polytechnic University of Marche, Ancona, Italy

Abstract

In most areas of the world, celiac disease (CD) is one of the commonest life-long disorders showing an overall prevalence of 1%–2%. This high and raising prevalence could be related to the general increase of autoimmune diseases related to shifts in the immune response secondary to reduced frequency and severity of infectious diseases (so called hygiene hypothesis) and/or changes in the intestinal microbiome. Despite a significant increase in the incidence of clinically diagnosed CD, largely related to the diffusion of simple and sensitive diagnostic tools and increased awareness of CD clinical polymorphism, still a significant proportion of cases (>50% on average with spikes of >90% in some areas) remains undiagnosed in most countries.

A policy of case-finding is currently considered the best buy for improving the CD detection rate, however, this strategy has significant limitations. Targeted screening of genetically predisposed individuals could represent the road ahead for an efficient intervention of CD secondary prevention.

Keywords

Epidemiology; risk factor; diagnostic procedure; epidemiological research; population; demography; geography; celiac disease; incidence; prevalence; screening; case-finding

1.1 Introduction

The distribution of celiac disease (CD) over space and time has attracted the interest of researchers since the early knowledge of this condition. During the first half of the 20th century, CD was regarded as a rare disease in most Western countries, with an estimated prevalence of 1:4000–1:8000 and the notable exception of Western Ireland where a frequency of one every 400 young children, for some unknown reason/s, was reported (Mylotte et al., 1973). At that time, it was postulated that the higher prevalence of CD in the North-West of Europe was somewhat related to the higher frequency of HLA-related predisposing genotypes, along a South-East/North-West gradient from the Middle East area (Cronin & Shanahan, 2001).

The subsequent evolution of research, particularly the development of sensitive and simple diagnostic tools, particularly the IgA class antitissue transglutaminase (tTG) antibodies, unmasked a completely different story: (1) CD is one of the commonest life-long disorders, with an average prevalence of 1% in the general population and a higher frequency in well-defined at risk groups, such as relatives of affected individuals and patients with autoimmune comorbidities; (2) the disease has a worldwide distribution, even though the local prevalence varies according to genetic and environmental factors; (3) still today, due to huge clinical variability, most CD cases escape diagnosis unless actively searched by proactive policies, such as mass screening in the pediatric age group (Catassi et al., 2022).

In this chapter we will review the epidemiology of CD in the world, as described by the incidence, the prevalence, and the changes over time of these parameters in the general population. The analysis of these dynamic data will show how the knowledge of CD epidemiology may contribute to the understanding of the etiology of the disease and to the development of preventive strategies.

1.1.1 Definitions

For the sake of clarity, we define here the terms that will be repeatedly used throughout this chapter.

CD. Patients who have been diagnosed with CD according to currently available diagnostic guidelines. In adults, the diagnostic algorithm include both the positivity of serum celiac autoantibodies and the finding of villus atrophy (grade 3A to 3C lesion according to the Marsh-Oberhuber criteria) at the small intestinal biopsy. In children, the biopsy may or may not be required, according to the levels of the celiac autoantibodies.

Potential CD. Positivity of serological CD markers, particularly of IgA anti-tTG and antiendomysial (EMA) antibodies, in a patient with a normal histological picture (grade 0 or grade 1 lesion) at the small intestinal biopsy (Catassi et al., 2022).

Celiac autoimmunity. Positivity of serological CD markers, particularly of IgA anti-tTG and antiendomysial (EMA) antibodies (small intestinal biopsy not performed).

Prevalence of CD. The total number of individuals in a population who have CD at a specific period of time, usually expressed as a percentage of the population.

Incidence of CD. The number of individuals who are newly diagnosed with CD during a particular time-period (usually a year).

CD detection rate. The proportion of CD cases that are diagnosed on clinical basis, as compared to the overall prevalence of the disease in a given population.

Screening. Presumptive identification of unrecognized disease by the application of tests, examinations, or other procedures which can be applied rapidly. Screening tests sort out apparently well persons who probably have a disease from those who probably do not. A screening test is not intended to be diagnostic. Persons with positive or suspicious findings must be referred for diagnosis and necessary treatment.

CD case-finding. The process of looking for disease identification among people who actively seek care due to symptoms compatible with CD. It is in principle, but not necessarily, a patient initiated pathway to diagnosis (Lönnroth et al., 2013). Passive Case Finding (PCF, from the patient to the doctor) is defined as a CD diagnosis at health facilities among individuals who are aware of their symptoms and present for evaluation of the same on their own, while Active Case Finding (ACF, from the doctor to the patient) is the systematic CD testing of all individuals who are at risk of developing this disorder (Saini & Garg, 2020), due to the presence of one or more symptoms/conditions/comorbidities correlated to CD.

1.2 Incidence of celiac disease

Although apparently simple to measure, the evaluation of CD incidence requires a well-organized system of data collection about new cases of disease and the referral population (an example of this is the Swedish National Celiac Disease Register established in 1998), which is not available in many countries. For this reason, CD incidence cannot be calculated in many areas of the world.

In Western countries, a recent systematic review and meta-analysis reported the pooled incidence of CD in women and men to be 17.4 (95% CI: 13.7, 21.1) and 7.8 (95% CI: 6.3, 9.2) per 100,000 person-years, respectively. CD incidence has largely increased during the last decades in these countries (King et al., 2020). During the period 2010–14, twenty times more CD patients were diagnosed than during 1975–79 in the United Kingdom. The largest increase in diagnosis rates occurred in young women, the elderly, and the Asian immigrants (Holmes & Muirhead, 2017). In children, large increases in the incidence of CD across Europe have reached 50 per 100,000 person-years in Scandinavia and Spain with stabilization in some (notably Sweden and Finland). Larger increases in incidence have been found in older age groups than in infants and ages <5 years (Roberts et al., 2021). In the United States (Olmsted County, Minnesota) the overall age- and sex-adjusted incidence of CD increased from 11.1 per 100,000 persons/year in 2000–01 to 17.3 in 2008–10. Interestingly, the relative frequency of classical CD among incident cases decreased over time between 2000 and 2010 (Ludvigsson et al., 2013). The previously mentioned meta-analysis also found that the average annual incidence of CD in Europe, North America and Oceania has been rising over the past several decades by 7.5% (95% CI: 5.8, 9.3) per year (King et al., 2020). On the other hand, epidemiological data on CD incidence are still lacking for many countries (e.g., India, China, and Russia).

The increasing incidence of CD should not be interpreted as an evidence of higher frequency of the disease. This finding is primarily related to the improvement of the diagnostic rate, which in turn depends on both improved diagnostics, particularly diffuse availability of sensitive and simple serological test such as the anti-tTG antibody determination, and increased awareness of the high clinical variability of the disease among physicians and the general population.

1.3 Prevalence of celiac disease in the world

The frequency of CD is properly described by its prevalence, as determined by studies on samples of the general population, for example, school-age children performing the first-level test at school. Fig. 1.1 shows data on CD prevalence in different countries.

Figure 1.1 Prevalence of CD in different countries.

Schematic representation of the prevalence of CD in different countries. From Lionetti and Catassi (2014). Co-localization of gluten consumption and HLA-DQ2 and -DQ8 genotypes, a clue to the history of celiac disease. Digestive and Liver Disease, 46(12), 1057–1063. https://doi.org/10.1016/j.dld.2014.08.002. No changes were made to the Figure. Creative Common License found at https://www.sciencedirect.com/science/article/pii/S1590865814006008?via%3Dihub.

A recent systematic review and meta-analysis found the pooled world prevalence of CD autoimmunity to be 1.4% [95% confidence interval (CI): 1.1%–1.7%], based on positive results from tests for IgA anti-tTG ab and/or EMA. The prevalence of CD autoimmunity varied from continent to continent, highest being in Europe and Asia. The pooled global prevalence of biopsy-confirmed CD was 0.7% (95% CI: 0.5%–0.9%) with regional variations (0.4% in South America, 0.5% in Africa and North America, 0.6% in Asia, and 0.8% in Europe and Oceania). The prevalence of CD was significantly higher in females than in males (0.6% vs 0.4%), and in children than in adults (0.9% vs 0.5%)(Makharia et al., 2022; Singh et al., 2018).

Wide variations of CD prevalence in Europe were reported in the year 2010, with an overall estimate of 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) (Mustalahti et al., 2010). More recently, the prevalence of previously undiagnosed CD from screening surveys (histology based) in Europe ranged from 0.10% to 3.03% (median=0.70%), with a significantly increasing annual trend. Prevalence since 2000 was significantly higher in northern Europe (1.60%) than in eastern (0.98%), southern (0.69%) and western (0.60%) Europe (Roberts et al., 2021). In two different birth cohorts of 12-years old Swedish students the overall prevalence of CD was 2.2 and 2.9%, respectively (Ivarsson et al., 2013). In Tromsø, Norway, 12,981 adults participated in a population-based CD serological screening. The prevalence of previously diagnosed CD was 0.37%. Additionally, the prevalence of previously undiagnosed CD was 1.10%. Thus 1.47% of this Norvegian population sample had CD, of whom 75% were previously undiagnosed (Kvamme et al., 2022). In a large pediatric CD screening performed in Italy on 9006 school age children the overall prevalence of CD was 1.62% (see details of this study in paragraph 5) (Lionetti et al., 2023).

In a large multicentre study performed in the United States in the early 2000s, Fasano and coworkers found a CD prevalence of 0.75% in a sample of 4126 subjects (Fasano et al., 2003). More recently, in a sample of 30,425 adults resident in Olmsted County (Minnesota, United States) the estimated prevalence of CD was 1.1% (95% CI: 1.0%–1.2%) (Choung et al., 2017). The analysis of data collected in the United States National Health and Nutrition Examination Survey, from 2009 through 2014, on 22,277 participants 6 years and older showed a 0.7% prevalence of CD. Interestingly, the disease was more common among individuals who lived at latitudes of 35–39 degrees North (odds ratio, 3.2; 95% CI: 1.4–7.1) or at latitudes of 40 degrees North or more (odds ratio, 5.4; 95% CI: 2.6–11.3) than individuals who lived at latitudes below 35 degrees North, independent of race or ethnicity, socioeconomic status, and body mass index (Unalp-Arida et al., 2017).

In Central and South America, Australia, North Africa and the Middle East areas, CD is as common as in the Western world (around 1% of the general population) (Ahadi et al., 2016; Alarida et al., 2011; Chin et al., 2009; Gandolfi et al., 2000; Israeli et al., 2010; Mora et al., 2012; Remes-Troche et al., 2006), while no data are available for Sub-Saharan African countries. An impressive prevalence of CD autoimmunity (5.6%) has been documented in the Arab population of Saharawi, probably related to the abrupt and recent changes in the dietary pattern of this population (from a low- to a high-gluten diet) (Catassi et al., 1999).

Currently a continent under deep investigation is Asia (Singh et al., 2016). Based on available data, three different pattern of CD epidemiology can be recognized in Asia: (1) areas with Western-type prevalence (e.g., Turkey, North-Western India, North-Western China), (2) areas with very low CD prevalence (<0.2%) due to the rice-based dietary pattern and overall low prevalence of HLA-DQ2/DQ8, for example, Vietnam, Philippines and Japan, and (3) unknown CD prevalence, for example, Russia, Central Asia and South-East Asia. In China, CD was mostly unknown in the past, however two recent population-based studies showed that this disorder is not uncommon in this country, particularly in north China, where wheat is a staple food (Fukunaga et al., 2020; Poddighe et al., 2019; Ramakrishna et al., 2016; Yuan et al., 2017; Zhou et al., 2020).

In summary, epidemiological studies performed during the last decades have shown that wherever gluten-containing cereals (particularly wheat) are staple food, which is the case in most world countries, CD is a common disease affecting around 1% of the general population, with significant variations between countries and a definitely higher prevalence in some areas, such as Sweden and Italy.

1.4 Factors influencing the prevalence of celiac disease

Generally speaking, the between-countries variability of CD prevalence may depend on spurious (1) or true (2) differences:

1. Spurious differences. Factors related to the study-design may heavily influence the prevalence of the disease, such as: (a) age of investigated subjects (higher prevalence in children than in adults); (b) gender distribution (CD is more common in females); (c) selection bias in the sampled population. For instance, the prevalence of CD may be underestimated in screening studies performed in blood donors, representing the healthier segment of the population, or overestimated in selected groups of subjects such as patients seen at the general gastroenterology clinic; (d) study-protocol and screening test. Pioneer CD screening studies using the antigliadin antibody (AGA) as first-level screening test underestimated CD prevalence, as compared to an anti-tTG based screening, by nearly 40% (Gatti et al., 2020); (e) diagnostic criteria. The prevalence of CD is usually lower in studies requiring evidence of the celiac enteropathy at the small intestinal biopsy for diagnosis (cases of potential CD may be excluded from prevalence calculation).

2. True differences. On the other hand, the true prevalence of CD is directly related to the population prevalence of the CD-predisposing genotypes HLA-DQ2 and -DQ8 (30%–40% in most countries) and to the average level of wheat consumed at the population level. This is clearly exemplified by data from India: CD is much more common (0.9%) in the Northern part of the country, where wheat is the staple food, than in the Southern part (0.01%) showing both a lower prevalence of HLA-DQ2 genotype and a lower wheat consumption (Ramakrishna et al., 2016; Verma et al., 2022). Likewise, higher consumption of gluten-containing food could explain the higher prevalence of CD found in the South of Italy (1.93%) as compared to Central Italy (1.36%) (Lionetti et al., 2023). Interestingly, on a global scale HLA-DQ2 prevalence and amount of gluten consumption apparently show a positive correlation throughout the world (for possible explanations of this finding see paragraph 6.1) (Lionetti & Catassi, 2014).

1.5 Pediatric screening for celiac disease: lessons from the Italian studies

Italy is not only the country where the first mass screening project for CD in children was implemented in the early 90 s (Catassi et al., 1994), but also the homeland of several CD pediatric screening performed during these last 30 years. In all these studies a first-level screening test was performed at school and a complete CD diagnostic algorithm was activated in screening-positive subjects. The analysis of these studies allows a depiction of the evolving epidemiology of this common condition.

In a multicenter, countrywide study performed in the years 1992–94, 17,201 students aged 6–15 years underwent CD screening by the combined determination of serum IgG- and IgA-AGA test. CD was diagnosed in 82 subjects. The prevalence of undiagnosed CD was 0.48%, 1 in 210 subjects. The overall prevalence of CD, including previously diagnosed CD cases, was 0.54%, that is, one in 184 subjects. The ratio of known to undiagnosed CD cases was 1–7 (Catassi et al., 1996). As shown many years later by a validation study, the IgA AGA test, as compared to an IgA anti-tTG screening, underestimated CD prevalence by 39%. After adjustment for this underestimation, the 1992–94 CD prevalence was 0.88% (Gatti et al., 2020). During the period 1999–2001, 3541 subjects (1500 from continental Italy and 2041 from Sardinia) were screened for CD using IgA anti-tTG antibodies as first-level tests. A diagnosis of CD was made in 25 subjects, that is, an overall prevalence of 1:126 individuals (0.79%) (Fabiani et al., 2004). Another anti-tTG–based screening study performed on Italian children in 1999–2000 reported a CD prevalence of 1.1%, slightly higher than the 1993–95 estimate but definitely lower than the CD prevalence found in recent studies (Tommasini et al., 2004). During the years 2015–20 a large nationwide multicenter CD screening was again performed in 9008 school-age children (5–11 years of age) screened at school in eight different towns. This time the first level screening test was the determination of HLA-related predisposing genotypes HLA-DQ2 and -DQ8 (Fig. 1.2).

Figure 1.2 Diagnostic algorithm used in recent CD screening studies in Italy.

Flow-chart showing the diagnostic algorithm used in recent CD screening studies in Italy. tTG-IgA= antitissue transglutaminase of IgA class; t IgA=total serum IgA; CD=celiac disease; EMA=antiendomysial antibodies.

In this recent study the overall prevalence of CD in Italy was 1.62% (95% CI,1.39–1.86), 1.62% (95% CI 1.25–2.06) in the North of Italy, 1.36% (95% CI 1.04–1.75) in the Center, and 1.93% (95% CI 1.50–2.45) in the South, with a statistically significant difference between Central and South Italy (p=0.0482) (Fig. 1.3).

Figure 1.3 Prevalence of CD in Italy.

Prevalence of CD in different areas of Italy, in a sample of 9006 school age children screened by the algorithm shown in the previous figure. From Lionetti et al. (2023). Prevalence and detection rate of celiac disease in Italy: Results of a SIGENP multicenter screening in school-age children. Dig Liver Dis, 2023(22), 871–874. No changes were made to the Figure. Creative Common License found at: https://www.sciencedirect.com/science/article/pii/S1590865822008714?via%3Dihub.

The percentage of CD cases diagnosed prior to the school screening, that is, the so-called visible part of the CD iceberg, was only 35% (Lionetti et al., 2023).

Based on the above data, there is little doubt that a significant increase of childhood CD prevalence in childhood took place in Italy during the last 30 years. The reason/s for the linear increase of CD prevalence in Italian children during the last decades remain/s unclear. Changes of the major determinants of CD, namely host genetic make-up and gluten consumption, are unlikely to explain this finding. Although increasing immigration from extra-European countries occurred during these last decades in Italy, only 11.5% of the most recent study groups were nonwhite children. Furthermore, most of these non-European children originated from Asian and South American countries, that is, areas generally showing a prevalence of CD lower than Europe (Lionetti et al., 2023). As for consumption of wheat derivatives, food supply data, if anything, indicate a decreasing trend in the consumption of gluten-containing products by the Italian population (Data Available at http://Www.Fao.Org/Faostat, n.d.). Likewise, we are unaware of any recent change of other environmental CD potential risk factors, for example, early dietary habits, early gluten composition, dough fermentation, intestinal infections, and drug use/abuse.

The recent Italian CD screening studies also shed a light on the sensitivity of the CD case-finding approach, as well as the different performances of an active vs a passive case-finding policy. In this population sample there were 157 children with CD: (1) 55 (35%) had received a clinical diagnosis of CD prior to the screening (by means of a PCF process); (2) 59 cases (38%) were found among screened students presenting at least one of the condition listed in the criteria for CD case-finding (an ACF process); (3) 43 cases (27%) were detected among screened children showing no indication to CD case-finding (diagnosis only by mass screening) (Fig. 1.4).

Figure 1.4 Representation of the celiac iceberg.

The celiac iceberg in Italy, as seen by the 2015–20 studies. PCF=passive case-finding; ACF=active case-finding; MS=mass screening. Data from Catassi et al. (2023). Celiac Disease detection strategies: poor performance of the case-finding policy. Am J Gastroenterol, 2023.

Positivity of at least one criterion for CD case finding was found in 53% of all screened subjects. There was only a minimal, statistically not significant difference in the prevalence of CD between HLA positive children with at least one (3.39%) and those with no criterion for CD case-finding (2.83%) (p=0.419).

Put in the context of a country characterized by high awareness of CD clinical polymorphism among doctors and free availability of a primary care pediatrician for all children, these simple findings highlight that: (1) a PCF policy detects only about one third of CD cases; (2) a proactive CF policy (ACF) still does not intercept >25% of CD cases; (3) even more importantly, the ACF is not selective (requires testing more than 50% of the general pediatric population) and is not significantly more efficient than a by-chance testing. Due to the possible negative consequences of delayed/missed CD diagnoses (Al-Toma et al., 2019) we believe that these results suggest considering the implementation of simple mass CD screening programs, particularly focused on the pediatric age-group (Catassi et al., 2023).

1.6 Is the prevalence of celiac disease changing over time?

1.6.1 In the ancient time

The history of Homo sapiens dates back to about 200,000 years ago (200 KYA), however CD is a modern disease appearing on the stage only after gluten-containing cereals were introduced in the human diet around 12 KYA with the agricoltural revolution. Aretaeus of Cappadocia, living in the 2nd century AD, recorded a malabsorptive syndrome with chronic diarrhea, causing a debilitation of the whole body that he named the Celiac affection (Catassi et al., 2022). However there are no reports on CD in the ancient time, apart from the anecdotal description of a possible disease-case in a young woman died in Italy during the first century AD. Her mummy presented evidence of CD manifestations, particularly short height (140 cm), dental enamel hypoplasia, skeletal signs of anemia (cribra orbitalia), and a decreased bone mass with osteoporosis and bone fragility (Gasbarrini et al., 2010). Interestingly, the analysis of DNA extracted from a bone sample and a tooth of this mummy displayed the haplotype HLA-DQ 2.5 associated to the highest risk of CD (Gasbarrini et al., 2012).

The extreme rarity of CD in the ancient time is indirectly suggested by the analysis of the current geographical distribution of HLA CD-predisposing genotypes and the world distribution of wheat consumption. As previously anticipated, domestication of gluten-containing cereals (particularly ancient varieties of wheat and barley) began approximately 12 KYA in Neolithic settlements in the north-eastern (Turkey, Iran, and Iraq) and in the south-western (Palestine, Syria, and Lebanon) regions of the so-called Fertile Crescent area. Cultivation of wheat and barley slowly spread northwest ward across Europe to reach Western countries, as Britain, only 4 KYA (Ammerman & Cavalli-Sforza, 1984). The agriculture revolution paved the way to new diseases, such as CD. Since treatment with the gluten-free diet was not available in the ancient time, the CD predisposing genotype could exert a negative impact on human reproductive fitness and survival over thousand years. As a consequence of a prolonged negative selective pressure, CD and its predisposing genotypes should be less common in Middle East than in European countries (as originally theorized by Simoons) (Lionetti & Catassi, 2014; Simoons, 1981). On the other hand, nowadays CD is equally common, for instance, in United Kingdom and Turkey, and the frequency of HLA-DQ2 (the major CD-predisposing haplotype) shows a positive correlation with the amount of gluten consumed in different world countries (Fig. 1.5)

Figure 1.5 Relation between HLA-DQ2 and gluten consumption.

There is a positive linear correlation between the prevalence of HLA-DQ2 genotype and the mean gluten consumption in different countries From Lionetti and Catassi (2014). Co-localization of gluten consumption and HLA-DQ2 and -DQ8 genotypes, a clue to the history of celiac disease. Digestive and Liver Disease, 46(12), 1057–1063. https://doi.org/10.1016/j.dld.2014.08.002. No changes were made to the Figure. Creative Common License found at: https://www.sciencedirect.com/science/article/pii/S1590865814006008?via%3Dihub.

and is even higher in Turkey and Iran, that is, countries consuming more wheat and for a longer duration of time, than in Finland and Ireland, that is, countries consuming gluten during a shorter time span. To explain these counterintuitive findings, we suggested that the diffusion of HLA CD-predisposing genotypes and that of CD occurred in different time periods. The currently high prevalence of CD is most likely a recent event that took place only in the last centuries/decades and is possibly explained by environmental conditions, such as higher susceptibility toward autoimmune diseases caused by reduced frequency and severity of infections (so-called hygiene hypothesis) and/or changes in the intestinal microbiome (Lionetti & Catassi, 2014).

1.6.2 In the modern time

The pediatrician Samuel Gee gave the first modern-day description of CD in children in a lecture at Hospital for Sick Children, Great Ormond Street, London, in 1887. However, the first data on CD prevalence in the general population became available only one hundred years later, following the introduction of simple and sensitive serological diagnostic tests for CD.

We already discussed in paragraph 5 the evidences showing that in Italy the prevalence of CD almost doubled over the last 30 years. What has happened in other parts of the world? Data collected at different time-points are available for some countries. In the United States, we analyzed sera from 3511 adults resident in Washington County, Maryland, with matched samples from 1974 (CLUE study I) and 1989 (CLUE study II). CD autoimmunity was detected in seven subjects in 1974 (prevalence 1:501) and in an additional nine subjects in 1989 (prevalence 1:219). During a 15-year period CD prevalence increased twofold in the CLUE cohort and fivefold in the United States from 1974 to the year 2000 (from 0.2% to 1%) (Catassi et al., 2010). Recently, 23,400 children from general population in Denver metropolitan area were enrolled in the ASK study from 2016 to 2019, and 23,319 participant children had the IgA antitransglutaminase tested. Of these, 2% showed positivity of celiac autoimmunity by both the chemiluminescence and the radioimmunoassay antibody determination (He et al., 2020). Although the prevalence of celiac autoimmunity (instead than biopsy-proven CD) tends to overestimate the prevalence of CD, it is easy to notice a linear trend of a marked increase in the prevalence of CD in the United States during the last 50 years.

An interesting clue to the understanding of the causes of the recent surge of CD prevalence observed in some countries is provided by a CD screening study performed in school-age children living in adjacent Russian Karelia (n=1988) and Finland (n=3654). These populations are equally exposed to grain products and partly share the same ancestry, but live in completely different socioeconomic environments. Anti-tTG antibodies were less frequent in Russian Karelia than in Finland (0.6% vs 1.4%, p=0.005). CD was confirmed by duodenal biopsy in four of the eight anti-tTG IgA positive Karelian children, giving a prevalence of 1 in 496 compared to 1 in 107 children in Finland. Authors suggested that the lower prevalence of CD autoimmunity and of CD itself in Russian Karelia than in Finland may be the consequence of a protective environment characterized by inferior prosperity and standard of hygiene in Karelia (Kondrashova et al., 2008).

On the other hand, stabilization or even decrease in CD prevalence has also been observed in other places. As previously mentioned, between 1984 and 1986 Sweden experienced an epidemic of clinical CD in young children, attributed partly to changes in infant feeding. Later on, a two-phase cross sectional screening study was performed in which 13,279 12-years old children from two birth cohorts participated, born in 1993 and 1997, respectively. The total prevalence of CD was 2.9% and 2.2% for the 1993 and 1997 cohorts, respectively. The significant reduction of CD prevalence in the 1997 cohort was attributed to changes in infant feeding practices (Ivarsson et al., 2013). As a consequence of interventions aimed to primarily prevent CD development, the overall prevalence of CD could hopefully decrease in many countries.

1.7 How to improve the celiac disease detection rate (unraveling the celiac iceberg)

There is no doubt that the CD detection rate has increased in many countries over the last decades, particularly due to the adoption of case-finding policies and greater disease awareness. For instance, in Italy the CD detection rate was only 11% in the years 1992–94 and rose to 40% in 2015–20 (Gatti et al., 2020) (Lionetti et al., 2023). However, the percentage of cases that are currently diagnosed on clinical basis remains much smaller than the overall CD prevalence. This concept is often expressed by the picture of an iceberg that shows a visible part (the one diagnosed on clinical ground) and an even bigger submerged portion (the proportion of cases remaining undiagnosed) (Catassi, 2017). Even in countries showing a high level of CD awareness, on average 60%–70% of cases still remain undiagnosed and, being untreated, are exposed to the risk of long-term complications (Kvamme et al., 2022). In other countries, for example, India, the visible/diagnosed part of the CD iceberg is smaller than 5% (Ramakrishna et al., 2016).

How to approach the celiac iceberg is still a matter of debate, as discussed also in Chapter 8 of this book. Mass screening is highly sensitive and allows the detection of the large majority of CD cases together with an early treatment. If the screening is performed in the pediatric age group, it may prevent long-term complications (Catassi et al., 2022). However there are ethical and practical arguments against CD mass screening: (1) the advantages of an early diagnosis have not been entirely clarified; (2) life-long CD treatment by the gluten-free diet (GFD) may have a negative impact on the psycho-social aspects of daily life; (3) the GFD is associated with increased economic costs, both at the individual and societal level; (4) it remains arbitrary to establish the age of subjects at screening given that CD may develop at any age, as clearly shown by the previously mentioned American CLUE study (Catassi et al., 2010). Late CD sero-conversion in previously negative subjects has been shown by long-term follow-up studies of screened subjects, a finding that is however more common in at-risk individuals (e.g., relatives of CD patients) (Paavola et al., 2022) than in the general population (Sandström et al., 2022).

Most experts and international societies currently agree that CD case-finding (testing only cases belonging to at-risk groups) is the best option to detect subclinical CD (Husby et al., 2020; Ludvigsson et al., 2014; Rubio-Tapia et al., 2023). For instance, the recently updated guidelines for the diagnosis and management of CD of the American College of Gastroenterology state that mass screening of asymptomatic individuals is not supported because CD does not fulfill some of the major World Health Organization criteria for mass screening, specifically the criteria that the natural history of the condition, including development of latent-to-declared disease, should be adequately understood and there should be an agreed policy on whom to treat as patients. Case finding is the currently preferred strategy to increase detection of cases, although the pros and cons of this approach are still a matter of debate (Rubio-Tapia et al., 2023).

Case-finding is indeed ethically sound, cheap and cost-effective. However case-finding also has important limitations: (1) low sensitivity; (2) it may have a socio-economic bias; (3) up to 85% of patients eventually found by screening have suffered from unrecognized symptoms for some time—even for many years—before diagnosis (Popp et al., 2019). Furthermore, as discussed in paragraph 5, even a policy of active case-finding is not only difficult to implement in the context of many national health systems but also poorly sensitive and specific.

In order to definitely improve the CD diagnostic rate, it is our opinion that new policies should be tested in the near future, for instance based on: (1) early identification (e.g., at birth) of HLA genetically at-risk individuals with stratification of HLA risk, and (2) targeted periodic serological CD testing of genetically predisposed individuals, for example, at 5 and 10 years of age and then every 10 years (or whenever symptoms of suspected CD do appear) (Fig. 1.6).

Figure 1.6 CD screening algorithm.

Schematic representation of a proposed CD screening algorithm.

1.8 Conclusions

In most areas of the world, CD is one of the commonest life-long disorders showing a prevalence of 1%–2% in the general population. Even in areas currently characterized by a lower prevalence of disease, such as Eastern Asia, CD could become a frequent disorder due to the progressive Westernization of the diet on a worldwide basis. The reason/s of this high disease prevalence is/are still unclear, but could be related to the general increase of autoimmune diseases related to shifts in the immune response secondary to reduced frequency and severity of infectious diseases (so called hygiene hypothesis) and/or changes in the intestinal microbiome. Despite a significant increase in the incidence of clinically diagnosed CD, largely related to the diffusion of simple and sensitive diagnostic tools and increased awareness of CD clinical polymorphism, still a significant proportion of cases (>50% on average with spikes of >90% in some Asian areas) remains undiagnosed in many countries.

A careful policy of systematic case-finding is currently considered the best buy for improving the CD detection rate, however this policy has significant limitations. Targeted screening of genetically predisposed individuals could represent the road ahead for an efficient intervention of secondary prevention (early diagnosis) of CD.

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Chapter 2

Wheat gluten proteins: from taxonomy to toxic epitopes

Gianfranco Mamone¹, Luigia Di Stasio¹, Serena Vitale² and Carmen Gianfrani²,    ¹Institute of Food Science, Department of Biology, Agriculture and Food Sciences, National Research Council of Italy, Avellino, Italy,    ²Institute of Biochemistry and Cell Biology, Department of Biomedical Sciences, National Research Council of Italy, Naples, Italy

Abstract

Wheat is one of the most widely consumed cereals worldwide. However, wheat-based foods have to be strictly avoided by a substantial number of people suffering from celiac disease (CD), a gluten intolerance (approximately 1% of the general population). Gluten, the main seed storage protein, contains hundreds of highly homologous proteins characterized by high contents of glutamine and proline. This peculiar aminoacidic composition strongly hampered the physiologic digestion by gastrointestinal proteases, and large peptides with immunogenic potential are delivered in the gut, eliciting gut mucosa inflammation in CD patients. By using in vitro and in vivo assays, based on intestinal T cells and peripheral blood cells from CD patients after a brief gluten oral challenge, more than 50 different gluten peptides have been identified so far that elicit an inflammatory T-cell response in celiac. The comprehensive definition of the gluten epitope repertoire is crucial for designing immunological or enzymatic therapies as alternatives to the gluten-exclusion diet, as well as for obtaining wheat species naturally devoid of the immunogenic sequences, or resulting from gene silencing molecular engineering. Furthermore, the availability of wheat species with low immunotoxic gluten proteins, although not suitable for the diet of celiacs, could have important implications for disease prevention in genetically risky