Coeliac Disease and Gluten-Related Disorders

Coeliac Disease and Gluten-Related Disorders provides an updated and comprehensive overview on the crucial aspects and clinical management of gluten-related disorders. It provides an overview of the scientific background, mechanisms involved, and emphasizes the translational effect of research on clinical practice. Highlighted throughout are insights into future research areas likely to have a crucial impact in the clinical management of these common conditions. The book is perfect for researchers and gastroenterologists involved in Coeliac Disease and other gluten-related disorders.

• Presents both research and clinically based perspectives on the most relevant issues of gluten-related disorders
• Provides a wide-ranging discussion and the most updated opinions by international experts in the field of coeliac disease and gluten-related disorders
• Translates the latest research insights into practical suggestions for specialists

• Language: English
• Publisher: Academic Press
• Release date: Oct 12, 2021
• ISBN: 9780128215722

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Chapter 1

Epidemiology and clinical features of celiac disease in adults

Mahendra Singh Rajput, Ashish Chauhan, Govind K Makharia

Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India

Abstract

Celiac disease was once thought to affect people from European origin only but subsequently it was recognized that it affects Caucasians living in North America, Oceania, and even South America. Celiac disease is now known to affect non-Caucasian populations including Africans and Asians. Therefore, celiac disease has now become a global disease and it affects nearly one percent of world's population. Furthermore, a rise in both prevalence and incidence of celiac disease has been observed in many European countries and United States of America. Such a change in the epidemiology and better recognition of celiac disease has been possible because of following reasons. While making of diagnosis of celiac disease was much tedious in the past century, the diagnostic criteria are now much simplified with availability of reliable serological tests. It was believed that celiac disease was a disease of childhood but now, it is recognized that it affects people of any age group, including elderly. Furthermore, while it was believed that gluten hypersensitivity in celiac disease is limited to the small intestinal mucosa, there are now evidences suggesting that celiac disease is a systemic disease and it affects many other organs including skin, liver, bones and brain. Therefore, the spectrum of symptoms of celiac disease is wide including both gastrointestinal and extra-gastrointestinal. In this chapter, we have reviewed the epidemiology and clinical manifestations of celiac disease.

Keywords

Small intestine; Enteropathy; Extraintestinal; Prevalence; Malabsorption; Gluten; Global

1.1 Introduction

Celiac disease (CeD) is an autoimmune disease due to hyperreactivity to gluten in genetically susceptible individuals [1,2]. Until a few decades ago, CeD was considered to be an uncommon disease and it was thought to be limited to individuals of European ancestry [3]. Advancement in the knowledge about this disease over the past three decades has led this to the limelight from a fairly uncommon disease before the 1980s. The key advancements that lead to widespread recognition of CeD are summarized below (Fig. 1.1). Firstly, making a diagnosis of CeD was very tedious and it required three sequential intestinal mucosal biopsies including one at baseline showing villous atrophy, a second one demonstrating histological improvement on a gluten-free diet (GFD), and a third biopsy showing worsening of villous abnormalities upon reintroduction of gluten into the diet [4]. In most current guidelines, the diagnostic criteria have been simplified and the diagnosis of CeD can be made on the basis of a combination of a positive celiac-specific serologic test and small intestinal biopsy specimens showing villous abnormalities [1,2]. Furthermore, a diagnosis of CeD can also be made based on the presence of high titer of anti-tissue transglutaminase antibody (x10 folds) even without demonstration of villous abnormalities [5].

Figure 1.1 Changing epidemiology and clinics of celiac disease through the different ages. AGA- anti-gliadin antibodies, EMA- Endomysial antibody, anti-tTG - Antitransglutamiase, GFD - Gluten free diet.

Secondly, CeD was thought to be a disease in children and seen mainly by pediatricians, but now, CeD is diagnosed at any age group, including the elderly [5]. Thirdly, CeD was thought to affect only people of European origin and subsequently, CeD was recognized in Caucasians living in North America, Oceania, and even South America. Now, CeD is well-recognized in the non-Caucasian population including Africans and Asians. The evolution of CeD has been very interesting. Even in those countries where CeD was thought to be uncommon, CeD was found to be common once systematic population-based studies were conducted in those countries [6,7].

Fourthly, it was initially thought that gluten hypersensitivity in CeD is limited to the small intestinal mucosa and all other features are secondary to malabsorption caused by the disease, but it is now established that many of the features of gluten hypersensitivity such as dermatitis herpetiformis (DH) cannot be explained on the basis of malabsorption alone. It is now been widely accepted that many other organs such as skin, brain, and bones are affected in CeD with or without of intestinal involvement [8–11].

Fifthly, the discovery of reliable serologic tests such as antitissue transglutaminase antibody (IgA tTG Ab), antiendomysial antibody (EMA) or antideamidated gliadin peptide antibody (anti-DGP Ab) have not only allowed screening of high-risk groups for CeD, but also made it possible to estimate the true prevalence of CeD in the general population. And lastly, an increase in the awareness about this disease amongst healthcare professionals and amongst general population also played a big role in unravelling this hidden disease (Fig. 1.1).

1.2 Initial epidemiological studies based on clinical symptoms

One of the oldest epidemiologic studies on CeD was conducted in 1950 when the diagnosis of CeD was based entirely on the presence of typical gastrointestinal symptoms. These studies established the cumulative incidence of the disease in England and Wales as 1 in 8000, and that in Scotland in 1 in 4000 [12]. With the introduction of more specific tests for malabsorption and advent of intestinal biopsy, the awareness about CeD greatly increased, which led to an increase in the incidence of the disease in the 1970s to 1 in 450 from Ireland, Scotland, and Switzerland [13,14] (Fig. 1.1).

1.3 Modern epidemiological study based on the serological test

In 1996, a multicenter study from Italy using three-layered strategy including clinical screening, serological tests, and intestinal biopsies in the school children gave birth to the modern epidemiology of CeD. Amongst 17201 healthy Italian students, the overall prevalence of CeD was found to be 1 in 184. More interestingly, only 1 of 7 was previously diagnosed as CeD, highlighting a big iceberg phenomenon, where clinically detectable patients were just a few and a large number of subjects remained undetected. Ever since epidemiological studies started appearing from various countries of the world which are summarized in the following sections [15].

1.4 Global prevalence of CeD

The assessment of the prevalence of CeD is accomplished as seroprevalence of CeD (a proportion of people having positive anti-tTG Ab and /or anti-endomysial Ab) or prevalence of biopsy-confirmed CeD, where intestinal mucosal biopsies show villous abnormalities of modified Marsh grade 2 or more along with a positive serological test.

1.5 Global seroprevalence of CeD

A recent systematic review and meta-analysis of population-based studies, including 275818 subjects have shown that a pooled global seroprevalence of CeD in the general population is 1.4% (95% CI 1 1%, 1 7%) [7] (Fig. 1.2). The seroprevalence of CeD varies from continent to continent, highest being in Europe and Asia (Table 1.1) Furthermore, the seroprevalence also varies from country to country, highest being in Algeria, Czech Republic, India, Israel, Mexico, Malaysia, Saudi-Arabia, Sweden, Portugal, and Turkey and lowest in Estonia, Germany, Iceland, Libya, Poland, Republic of San Marino, Spain, and Switzerland [7].

Figure 1.2 Country-wise seroprevalence of CeD; Countries are stratified into 4 groups of percentiles representing the 0 to 25th percentile (light grey) to the 76th to 100th percentile (dark black). Countries with highest percentiles of seroprevalence (76th to 100th) include Algeria, Czech Republic, India, Israel, Mexico, Malaysia, Saudi-Arabia, Sweden, Portugal, and Turkey with lowest percentiles of seroprevalence (0th -25th) include Estonia, Germany, Iceland, Libya, Poland, Republic of San Marino, Spain and Switzerland. From Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. (c. 2018). Clinical Gastroenterology and Hepatology, 16 (6), 823-836. https://doi.org/10.1016/j.cgh.2017.06.037.

Table 1.1

1.6 Global prevalence of biopsy-confirmed CeD

The global pooled prevalence of biopsy-confirmed CeD has been shown to be 0•7% (95% CI 0•5%, 0•9%) [7] (Fig. 1.3). On stratification of countries into quintiles based on the prevalence of biopsy-confirmed CD, countries with the highest prevalence (76th to 100th quintile) include Argentina, Egypt, Hungary, Finland, India, New-Zealand and Sweden and the countries with the lowest prevalence (0 to 25th quintile) include Brazil, Germany, Republic of San Marino, Russia, and Tunisia (Fig. 1.3) [7].

Figure 1.3 Country-wise prevalence of biopsy-confirmed CeD; The prevalence was stratified into 4 groups of percentiles representing the 0 to 25th percentile (light grey) to the 76th to 100th percentile (dark black). The countries with highest percentiles (76th to 100th) include Argentina, Egypt, Hungary, Finland, India, New-Zealand, and Sweden and the countries with lowest percentiles (0th -25th) include Brazil, Germany, Republic of San Marino, Russia and Tunisia. From Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. (c. 2018). Clinical Gastroenterology and Hepatology, 16 (6), 823-836. https://doi.org/10.1016/j.cgh.2017.06.037.

Most population-based epidemiological studies on CeD prevalence are based on serological data, and the diagnosis of CeD in all seropositive patients has not been confirmed by invasive small intestinal mucosal biopsies. Therefore, the global pooled prevalence of biopsy-confirmed CeD, which is 0.7% (95% CI: 0.5–0.9%), is lower than the seroprevalence.

The epidemiology of CeD is still evolving and population-based data is still not available from many countries.

1.7 Prevalence of CeD by gender and age

CeD is more common in females (0•6 %; 95% CI 0•5%, 0•8%) than in males (0•4%, 95% CI 0•3%, 0•5%) [7]. Furthermore, CeD is more common in pediatric age group compared to that in adults 0•9% (95% CI 0•6, 1.3) vs 0•5% (95% CI 0•3, 0•8). (P<0.001) [7].

1.8 Continent wise prevalence of CeD

1.8.1 CeD in Europe

Initial studies of CeD prevalence in the general population have been published from many European countries. In a multi-national European study including Finland, Germany, Italy and UK, 29,212 subjects were tested for CeD by anti-tTG antibody, and all those who had either a positive or a borderline titer of anti-tTG Ab were further tested for EMA in serum. The overall prevalence CeD in this multinational study was found to be 1.0% (95% CI 0.9 - 1.1). Interestingly, the prevalence of CeD was not uniform in the four participating European countries, despite sharing a similar distribution of causal factors (level of gluten intake and frequency of HLA-DQ2 and -DQ8 genotype). The prevalence of CeD was 2.0% (95% CI 2.0 – 2.8) in Finland, 1.5 (95% CI 1.1-1.9) in UK, 0.7% (95% CI 0.4–1.0) in Italy, 0.3% in Germany (95% CI 0.1–0.5) [16]. Interestingly another study from Germany including 12741 participants aged 1 to 17 years has shown a prevalence of CeD of 0.9% [17]. Furthermore, continent wise systemic review and meta-analysis of 33 studies have shown the seroprevalence and prevalence of biopsy-confirmed of CeD in Europe to be 1.3% (95% 1.1-1.5) and 0.8% (95% 0.6-1.1), respectively [7].

1.8.2 Celiac disease in America (North and South America)

CeD had been considered to be an uncommon disease in America till 2003, the results of a prevalence study reporting 1 in 133 Americans having CeD, led to more widespread recognition of this disease in the United States (USA) [18]. The systematic review and meta-analysis of population-based studies including 7 studies and 17,778 subjects have revealed that the seroprevalence of CeD in North America is 1.4% (95% CI 0.7-2.2). There is a paucity of data on the prevalence of CeD based on biopsy confirmation.

CeD is well known in those South American countries that are populated by individuals of European origin, such as Brazil. In a study including 4405 subjects from Brazil, the overall seroprevalence and prevalence of biopsy confirmed CeD was 3.6 and 3.41 per 1000, respectively. Prevalence in adult and children was 2.11 and 5.44 per 1000, respectively [19]. As per the systematic review of the studies from South America, the pooled seroprevalence and prevalence of biopsy-confirmed CeD was 1.3% (95% 0.5-2.5) (11 studies and 20245 subjects screened) and 0.4% (0.1-0.6) (5 studies and 16550 subjects), respectively [7].

1.8.3 Prevalence of CeD in Oceania

As in the European countries, a population-based study from Australia including 3011 subjects showed the seroprevalence and biopsy-confirmed prevalence of CeD to be 1/251 and 1/430, respectively [20]. A similar population-based study done in New Zealand including 1064 subjects has shown the prevalence of CeD to be 1.1% [21].

1.8.4 Prevalence of CeD in Africa

The pooled seroprevalence (7 studies and 15,775 subjects) and prevalence of biopsy-confirmed CeD (4 studies and 7902 subjects) in African continent was shown to be 1.1% (95% CI 0.4-2.2) and 0.5% (95% CI 0.2-0.9) [7]. The Saharawi population of Arab-Berber origin, originally living in Western Sahara, has been reported to have the highest prevalence of CeD in the world. A study of 990 Saharawi children, showed the prevalence of CeD in this population to be 5.6% [22]. The reasons for the high prevalence of CeD in the Saharawi population are likely to be a high rate of consanguinity and high gluten consumption in this population. Some other prevalence studies done in Africa have shown a prevalence of CeD to be 0.5% in Egypt, 0.8% in Libya, and 0.6% in Tunisia [23,24].

1.8.5 Prevalence of CeD in Asia

Until recent times, CeD was considered extremely rare in Asia, and patients presenting with celiac-like symptoms (chronic diarrhea, malnutrition, abdominal distention, etc) were diagnosed usually as having tropical sprue or kwashiorkor [25]. After the widespread availability of serologic tests, multiple screening studies performed in different Asian countries such as Turkey, Iran, Israel, Jordan and India have shown that CeD is not an uncommon disorder and it is often underdiagnosed in Asia [26]. Due to the heterogeneity of populations, genetics, economic condition and dietary habits, the epidemiology of CeD varies according to the geographical areas of Asia taken into consideration [26].

In India, CeD has been recognized mainly in the Northern part of India, where wheat is the predominant cereal consumed and a population-based study including 2879 subjects showed a prevalence of CeD to be 1.04% (1 in 96) [27]. Later, a pan-India study including 23,331 healthy adults from 3 different regions of India, showed a regional variation in the prevalence of CeD. While the age-adjusted seroprevalence of CeD in Northern, North Eastern regions were 1.23% and 0.87%, respectively, it was only 0.10% in the Southern region, showing a Northern and Southern region gradient in the prevalence [28]. Since the prevalence of HLA-DQ2 and DQ8 haplotype was similar in all the three regions, this regional difference in the prevalence was attributed to the differences in the wheat (gluten) eating pattern, which was highest in Northern part of India and lowest in Southern part of India [28].

In a systematic review and meta-analysis, the prevalence studies from Asia were segregated into studies from Middle East (Iran, Turkey, Saudi Arabia, Israel, Jordan) and South East Asia (data from India, Malaysia and Egypt). The pooled seroprevalence and prevalence of biopsy-confirmed CeD in the Middle East region and South East Region of Asia has been reported to be 1.6% (95% CI 1.2-2.1) and 0.6% (95% CI 0.4-0.8), and 2.6% (95% CI 0.3-7.2) and 0.8% (0.4-1.4), respectively, which were quite similar to that is reported from many European countries [7].

While the epidemiology of CeD in China was largely unknown until recent years, except for a small case series. In a cross-sectional study including 19,778 Chinese adolescents and young adults (age 16-25 years) from 27 geographic regions in China were screened for CeD using a combination of IgG anti-DGP and IgA anti-tTG Ab. More than 2% (2.19%) of them were detected to have a positive one of the antibody including 1.8% for IgG anti DGP and 0.36% for IgA anti tTG. The prevalence of people with a positive antibody varied remarkably amongst different regions of China and it was 12 times higher in the Northern provinces, such as Shandong, Shaanxi, and Henan, where wheat was the staple diet [29]. In another recent study including 2277 in-patients with gastrointestinal symptoms in four major ethnic groups of Xinjiang Uyghur Autonomous Region of China (including 1391 Han, 608 Uyghur,146 Kazakh and 132 Hui), the seroprevalence and prevalence of biopsy-confirmed CeD was observed to be 1.27% (95% CI, 0.81-1.73%), and 0.35% (95% Cl, 0.11-0.59%), respectively [30]. CeD was found to be three times more common in rural part with significantly higher wheat consumption compared to urban living subjects (3.16% vs 0.97%, P < 0.01). Interestingly, of 246 patients with diarrhea-predominant IBS in China, 2.85% were reported to have CeD [31]. These preliminary studies have established the foundation for exploration of the exact prevalence of CeD and regional geographical differences in the prevalence of CeD in China.

In a pilot study including 562 young healthy volunteers from Malaysia, the seroprevalence of CeD was found to be 1.25% (95% CI 0.78-1.72%). In this multi-ethnic country, all three ethnic groups such as Malay (0.8%), Chinese (1.7%) and Indian (1.3%) were affected [32]. In a study from Japan including 2008 subjects, anti-tTG Ab was found to be in a high proportion (8%), none of them, however, was EMA positive and only one showed celiac-type alterations at the small intestinal biopsy [33]. Similarly, in a study including 1961 Vietnamese children the seroprevalence based on anti-tTG Ab was observed to be 1%, but none of them was EMA positive [34].

While there are also reports of CeD from other Asian countries such as Pakistan, Bangladesh, Singapore, there are no formal reports on CeD from Indonesia, Korea, Taiwan and many other Asian nations [35,26].

1.8.6 Increase in the global prevalence of CeD over time

A study from the United States has shown that the prevalence of CeD was only 0.2% in the year 1975, but over past 25-30 years, it has increased by five-folds [36]. The pooled prevalence of CeD has increased from 0.6% (95% CI, 0.5%–0.7%) during the period of 1991-2000 to 0.8% (95% CI, 0.5%–1%) during 2011-2016 [7]. Furthermore, the increase in the prevalence over time is not limited to the United States and Europe, but it has been reported also in other parts of the world [37].

Although the prevalence of CeD in the general population has increased, the disorder still remains heavily underdiagnosed. It has been estimated that approximately five to ten patients remain undiagnosed for one diagnosed patient with CeD. This happens because a large proportion of patients with CeD have either atypical symptoms or minimal symptoms or they can even be asymptomatic. The diagnostic rate of CeD depends mostly on the level of awareness of the physicians. Despite an increase in the prevalence of CeD, and presence of a large pool of patients with CeD globally, the majority of patients (83%–95%) in developed countries, and possibly even a higher number in developing countries, still remain undiagnosed [38,40‐‐42].

1.8.7 Increase in the incidence of CeD

Not only the prevalence but the incidence of CeD has also increased throughout the Western world. The pooled average annual incidence of CeD has been estimated to be rising by 7.5% (95% CI: 5.8, 9.3) per year over the past several decades. A recent systematic review reported the pooled incidence of CeD 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 [37]. The increase in the incidence in CeD is both due to improved diagnostics and awareness about the disease amongst the physicians and changes in our environment and eating practices [38].

1.8.8 Spectrum of clinical manifestations of CeD

CeD is now considered a systemic disorder and their clinical presentation may be with gastrointestinal symptoms, called classical CeD accounting for 50-60% of all cases and non-gastrointestinal symptoms called non-classical CeD accounting for 40-50% of cases [39]. While some patients with CeD have fully expressed disease and present early in life, while in others the disease is expressed in a milder form and hence does not come to clinical attention till adulthood. Additionally, there are situations where the clinical presentation of CeD is abrupt and explosive in a relatively asymptomatic individual, which partly may be due to either occurrence of a second hit or the development of a complication.

1.8.9 Gastrointestinal manifestations (Classical CeD)

Many adult patients with CeD present with classical GI symptoms including chronic or intermittent diarrhea, steatorrhea, abdominal bloating, flatulence, and weight loss [40]. Some of the patients with CeD may have mild GI manifestations such as altered bowel activity, abdominal pain/discomfort, and bloating, and with this symptom complex, they are likely to be labeled as having functional gastrointestinal diseases including irritable bowel syndrome (IBS). In a meta-analysis of 22 eligible studies including 6991 patients with IBS, Ford et al. reported that 3.3% (95 % CI 2.3%, 4.5%) of them had CeD [41]. As one can expect, the prevalence of CeD is highest amongst patients with IBS-diarrhea predominant (pooled prevalence of 5.4%, 95% CI 3.3-7.8%) and IBS-Mixed suggesting that all patients with IBS-D and IBS-M should be screened for CeD [41]. Furthermore, the seroprevalence of CeD in patients with functional dyspepsia is higher (7.9% vs 3.9%) as compared with controls [42].

1.9 Extra-intestinal manifestations of CeD (Table 1.2 and Table 1.3)

Table 1.2

Table 1.3

1.9.1 Hematological manifestations

Anaemia is a common manifestation of CeD affecting approximately 12-69% in the western countries and 85-90% of Indian patients with CeD. Iron deficiency could be the sole manifestation of CeD even in the absence of diarrhea [48–56]. Iron deficiency is the commonest form of anaemia in CeD [43,44]. Although symptomatic B12 deficiency is uncommon, 8% to 41% of patients with CeD, however, have been detected to have vitamin B12 deficiency at the time of diagnosis [45–47]. The exact reason for deficiency of vitamin B12 is not known. However, it may be due to under-secretion of gastric acid, bacterial overgrowth, and occurrence of co-existent autoimmune gastritis. Folate deficiency has also been reported in patients with CeD [45,48]. Anemia in patients with CeD has been shown to respond very well to GFD and iron/vitamin supplementation [44,45]. Recent pieces of evidence suggest that CeD patients with anaemia have a significantly longer duration of symptoms, lower albumin levels, higher anti-tTG antibody level, and more often advanced enteropathy in comparison to CeD patients having normal hemoglobin [49].

On the other hand, 3.2% (95% CI 2.6% to 3.9%) of patients with iron deficiency anaemia (1 in 31) have CeD, as shown in a meta-analysis of 18 studies including 2998 patients with iron deficiency anemia [50].

The haematological manifestations of CeD are not limited to anaemia but other cell lines and coagulation cascade are also affected [45]. Up to 60% of CeD patients can have thrombocytosis but only a minority of patients have thrombocytopenia [52]. Thrombocytosis is believed to occur due to presence of an active inflammatory state, iron deficiency state and hyposplenism [45]. Venous thromboembolism has been well reported in CeD and there are reports describing co-occurrence of CeD and hepatic venous outflow tract obstruction [45,51,52].

1.9.2 Endocrinological manifestations

As CeD affects the early part of life, growth failure/retardation is an important manifestation of CeD. It is interesting to mention that while the height of men with CeD is slightly shorter, the women with CeD are taller than the respective control population [53]. The short stature is more common in those diagnosed during childhood and during adolescence than those diagnosed in adulthood. Such an event may occur because of multiple reasons. Those having the severe disease are more likely to be symptomatic and hence they come to clinical attention early, whereas those with mild disease may remain unnoticed in childhood and later diagnosed in adulthood. More importantly, the institution of a GFD in these patients is associated with early catch-up growth for the initial 2-3 years [54,55]. Early diagnosis and compliance with a GFD result in rapid recovery and patients may achieve normal adult height [56,57].

In a systematic review and meta-analysis involving 17 studies including 3759 patients with short stature, 7.4% (95% CI 4.7-10.6%) of all-cause short stature and 11.6% (95% CI 4.1-22.2%) of idiopathic short stature, respectively had biopsy-confirmed CeD [58]. The pathogenesis of short stature in patients with CeD is multi-factorial including malabsorption, lower levels of insulin like growth factor (IGF)-1, IGF-2, insulin like growth factor binding protein (IGFBP)-1 and IGFBP-3, partial insensitivity to the growth and concomitant hypothyroidism, hypogonadism and Turner's syndrome [59,60].

Association between CeD and type 1 diabetes (T1DM) and autoimmune thyroiditis is also well established. In a systematic review and meta-analysis, Elfstrom et al pooled the data from 27 studies involving 26,605 patients with T1DM and reported that 6% (95% CI 5-6.9%) of them have CeD. Thus, more than 1 in eighteen patients with T1DM have biopsy-confirmed CeD. The prevalence of CeD is lower in adults (2.7%, 95% CI 2.1-2.3%), than in children (6.2%, 95% CI 6.1-6.3%) with type 1 diabetes (P<0.001) [61].

As many as 10-15% of patients with CeD have co-existent clinical hypothyroidism or hyperthyroidism and conversely up to 2-4% of patients with autoimmune thyroid disorders have CeD [62]. In a recent systematic review and meta-analysis of 15 studies involving 6024 patients with autoimmune thyroid disorders, Roy et al reported that 1.4% (95% CI 1-1.8%) of them had biopsy-confirmed CeD [63]. The prevalence of CeD was lower in those with hypothyroidism (1.4%, 95% CI 1-1.9%) compared to those with hyperthyroidism (2.6%, 95% CI 0.7-4.4%)