Epidemiology of Celiac Disease

Abstract

Celiac disease (CD) is a chronic autoimmune disorder of the small bowel that is triggered by exposure to dietary gluten. In paediatric, CD commonly presents with intestinal manifestations, while in adults, many present with more subtle symptoms and extraintestinal manifestations, such as anaemia, fatigue, dermatitis, and headaches. The main scope of this chapter is to explore and present the prevalence of CD worldwide as well as trends in diagnosis over recent years. The prevalence of CD is approximately 0.5–1% in different regions of the world. However, exact prevalence rates may vary substantially in specific populations. Although CD was formerly believed to affect solely individuals of European ancestry, more recent studies indicate that the disease may have been either under-reported or undiagnosed in other populations. Moreover, it is possible that the increasing popularity of Western dietary practices may have an impact on the recent trend of increased rates of CD in non-Western populations. Certain population groups are also at high risk of developing CD, including first- or second-degree relatives of individuals with CD and those with diabetes or autoimmune disorders. Serological screening and HLA typing are therefore highly recommended for asymptomatic children in whom such risk factors are present.

1. Introduction

Celiac disease (CD), also known as gluten-sensitive enteropathy, is a chronic autoimmune disorder characterised by mucosal inflammation of the small intestine, villous atrophy, and crypt hyperplasia. It is triggered by exposure to dietary gluten and related proteins in genetically susceptible individuals [1]. Gluten is the major protein found in cereals, including wheat, rye, and barley, and possibly oats [2]. Manifestations of CD are typically classified as either intestinal or extraintestinal. Common intestinal manifestations include diarrhoea or constipation, loss of appetite and weight, bloating, flatulence, abdominal pain, and nausea/vomiting [3]. However, many patients may present with extraintestinal manifestations, such as anaemia, fatigue, loss of bone density, dermatitis, ulcers, and headaches [3, 4].

Because CD can have such a heterogenous and vague clinical presentation, in which some manifestations may present at different ages or overlap with other, unrelated disorders, many individuals often go undiagnosed [4]. Human leukocyte antigen (HLA) tests are utilised as markers of CD, as approximately 98% of individuals with CD are either HLA-DQ2- or HLA-DQ8-positive [5]. For a definitive diagnosis, an upper oesophagogastroduodenoscopy with a small bowel biopsy should be performed for any patients with positive serology or for those with a high probability of having the disease (>5%), regardless of serology results [6]. The main intervention for CD is a lifelong commitment to a gluten-free diet.

2. Epidemiology

The prevalence of CD has been estimated to range from 0.5–1% in different parts of the world [7]. Mass screening for CD in four general European populations revealed a prevalence of 1% [8]. On the other hand, information regarding the prevalence of CD in the Middle East and among Arab populations is scarce and primarily based on small-scale studies [9]. Interestingly, research shows that there is an increased prevalence of CD among women compared to men, with a male-to-female ratio of 1:2.8, thereby indicating that women are diagnosed two to three times more frequently than men, [10, 11, 12] except in the young and elderly in which there is a more equal sex distribution [13]. However, in population-based screening studies, males and females appear more evenly affected, [14, 15] suggesting either gender-based differences in the severity of symptoms or in terms of access to health care. Indeed, a previous study has shown that men demonstrate greater evidence of severe illness at presentation compared to women [12].

Historically, CD was believed to be limited only to Europeans or people of European origin (i.e., North Americans and Caucasian Australians); however, advances in the availability of serological testing for CD—for instance, anti-gliadin antibody (AGA), anti-endomysial antibody (AEMA), and anti-transglutaminase antibody assays—have shown that CD is common not only in those of European ethnicity, but also those originating from developing countries in which the major dietary staple is wheat [16, 17]. Epidemiological research conducted in areas thought to be free of CD, including the Middle East, South Asia, Africa, and South America, has indicated that the disease was previously under-diagnosed in these regions [18].

The recent increase in the frequency of CD diagnoses in these areas can be also explained by growing uptake of Western breastfeeding and dietary practices (i.e., either short-lived or absence of breastfeeding and early weaning in infanthood combined with a greater amount of gluten intake thereafter). This suggests that many individuals may have a genetic predisposition to CD, but that clinical presentation only occurs when there is sufficient gluten present in the diet [13]. Because CD is the result of an interaction between both genetic (with regards to both HLA- and non-HLA-associated genes) and environmental factors (i.e., exposure to and levels of consumption of gluten-containing grains), it would be reasonable to evaluate the global distribution of these two components in order to identify specific areas and populations at risk for CD [19].

2.1 Europe

Several epidemiological studies performed in Italy have indicated that the prevalence of CD ranges from 0.2% to 0.74% [20, 21, 22, 23]. However, studies from other European nations, including the United Kingdom, Sweden, Finland, and the Netherlands have reported slightly higher prevalence rates, ranging from 1.0% to 2.0% [24, 25, 26, 27, 28, 29].

2.2 North America

In the United States, the prevalence of adult CD is believed to be 0.95%, a rate similar to that reported in Europe, whereas the prevalence of paediatric CD has been calculated at 0.31%, with an overall prevalence ranging from 0.69% to 0.75% [14, 30, 31]. However, the prevalence of CD increases to 1.01% among non-Hispanic whites, with blacks and Hispanics in the United States showing considerably lower rates of CD at 0.3% and 0.2%, respectively [30, 32].

2.3 South America

The prevalence of CD in South America varies considerably between countries, despite their geographic proximity. In general, the prevalence of CD among Latin Americans is similar to that reported in Europeans. Overall, CD in Latin American populations is frequent and is primarily reported in populations and regions with Caucasian ancestry. Nevertheless, in certain countries with substantial Caucasian ancestry, such as Uruguay, the exact prevalence of CD remains unknown [33]. Studies conducted in Brazil have reported a prevalence of 1.5% in healthy blood donors [34, 35]. In an urban area of Argentina, the overall prevalence rate of CD among 2000 adults in the general population was 1:167, with the prevalence in women double that of men [36].

2.4 North Africa

In African populations, specifically in the Northern region of Africa, including Morocco, Algeria, Tunisia, Libya, and Egypt, the incidence of CD is very high and the disorder has been reported both in the general population and among at-risk groups [37, 38, 39]. Serological screening of 2500 Tunisian healthy blood donors showed that the prevalence of AEMAs in the general population was 1:355, which is close to that of Europeans. These high frequencies are not surprising given that wheat and barley are major staple foods in these countries and because there is high frequency of the HLA-DR3/DQ2 CD-predisposing haplotypes in these populations [38].

Another population in North Africa with an elevated prevalence of CD is the Saharawi people native to the western part of the Sahara desert; these individuals, many of whom live as refugees in Algeria, are of Arab and Berber origin and traditionally show a high degree of consanguinity. The elevated prevalence of CD in this population may be explained both by genetic factors, as the Saharawi population has a very high frequency of the HLA-DR3/DQ2 haplotype, and by environmental factors, because of changes in their dietary habits over the last few decades. For example, rates and duration of breastfeeding have been reduced and large amounts of gluten are now being consumed by infants and children in early life as part of their staple diet, due to food aid being supplied by Western countries as part of ongoing humanitarian programmes [40].

2.5 Asia

In the Asian Pacific islands (i.e., Indonesia, South Korea, and the Philippines), CD is likely to be rare because of the low wheat consumption in these populations and the low frequency of the HLA-DQB1*02 haplotype. In turn, in Southeast Asia, the HLA-DQB1*02 haplotype is often present in more than 5% of the population, but CD is nevertheless still predicted to be rare, as staple diets are traditionally based on rice [41]. In China, CD was previously thought to be uncommon; however, recent serological testing of adolescents and young adults in areas in which wheat is a dietary staple has indicated that the prevalence of the disorder may be as high as 0.76% [42].

2.6 The Middle East

Until the 1990s, CD was considered to be very rare in the Middle East. However, with the introduction of AEA and AGA testing, CD has been more readily reported from developing Middle Eastern countries at a rate similar to that of Western countries [43, 44, 45, 46]. However, this prevalence varies from 0.6% to 1.17% in low-risk populations, and from 2.4–19% in high-risk populations [47]. The prevalence of CD in Middle Eastern countries among low-risk populations is similar to that reported in Western countries, but is higher in high-risk populations, such as those with type 1 diabetes mellitus (T1DM). The frequency of the disorder is likely underestimated because of the lack of clinical suspicion and low patient awareness of the disease and its symptoms in this region of the world [47].

3. Trends over recent years

Over the last 50 years, the incidence of CD has steadily risen, and this may be only in part attributed to heightened clinician awareness and the advent of serological studies that can detect cases of what used to be subclinical disease. Environmental factors, such as gluten intake in infanthood, infections, and socioeconomic status may also play a role [48]. Serological screening studies have shown a dramatic increase in CD serology positivity over time [49, 50, 51, 52]. In a study by Rubio-Tapia et al., the researchers reported a four- to five-fold increase in CD over 50 years; [28] in addition, the prevalence of the disease appears to increase with age from 1% in children to 2.45% among an elderly cohort in Finland [28, 52].

Nonetheless, it remains true that the bulk of those with CD continue to go undiagnosed [24, 53]. Moreover, the rate of diagnosis varies in different countries, with a high in Finland in which about 70% of those with CD are diagnosed, [54] compared to the United States in which only 5% are diagnosed [53]. However, even within the United States, the rate of diagnosis has begun increasing in both adults and children [55, 56].

4. Risk groups

The prevalence of CD, as detected by screening programmes using specific antibodies, is substantially increased in several risk groups as compared with the general population. High-risk groups for CD include: first-degree relatives of individuals with CD (range: 5% to 7.5%), second-degree relatives of individuals with CD (range: 2–3%), and individuals with T1DM (range: 5–10%), Down syndrome (range: 5–12%), or autoimmune thyroid disease (range: 2–7%); in addition, CD is also associated with Turner syndrome (range: 4–8%), Williams syndrome, and selective immunoglobulin A deficiency (each with 8% risk) [14, 57, 58, 59, 60, 61, 62, 63]. Thus, because of their increased risk, routine screening for CD is recommended in asymptomatic children with these conditions.

The overall prevalence of CD is highly dependent on HLA-DQ2/DQ8 typing and gluten consumption. Individuals with positive HLA typing for CD have a high chance of developing symptoms when consuming high amounts of gluten. Moreover, those with diabetes, autoimmune disorders, or who are relatives of individuals with CD have an even higher risk of developing CD, since they also share the same HLA typing [7].

5. Conclusions

Globally, the prevalence of CD ranges from approximately 0.5–1% in different regions of the world. However, exact prevalence rates may vary substantially in specific populations. Although CD was formerly believed to affect solely individuals of European ancestry, more recent studies indicate that the disease may have been either under-reported or undiagnosed in other populations. Moreover, it is possible that the increasing popularity of Western breastfeeding and dietary practices may have an impact on the recent trend of increased rates of CD in non-Western populations. Certain population groups are also at high risk of developing CD, including first- or second-degree relatives of individuals with CD and those with diabetes or autoimmune disorders. Serological screening and HLA typing are therefore highly recommended for asymptomatic children in whom such risk factors are present.

Conflict of interest

The authors declare no conflicts of interest.

Abbreviations

AEMA	anti-endomysial antibody
AGA	anti-gliadin antibody
CD	celiac disease
HLA	human leukocyte antigen
T1DM	Type 1 diabetes mellitus