The Epidemiology of Celiac Disease in the General Population and High-Risk Groups in Arab Countries: A Systematic Review

Background and Aims Celiac disease (CD) is possibly the most common autoimmune disorder, which may lead to dietary problems in the Arab region. This paper is aimed at exploring the epidemiology of the celiac disease in Arab countries, including its prevalence, associated risk factors, and clinical patterns. Methods An extensive search of the literature was conducted from electronic databases such as PubMed, Embase, and Google Scholar. In total, 134 research papers were retrieved. We extracted studies published from January 1996 to December 2019. Our search was limited to studies published in English. Findings. The review included 35 studies with 22,340 participants from 12 countries and demonstrated a wide variation in the prevalence of CD. The highest prevalence among the general population (3.2%) was reported in Saudi Arabia, and the lowest (0.1%) was reported in Tunisia. Women demonstrated a higher prevalence of celiac disease relative to men. The peak age at diagnosis fell between 1 and 3 years and 9-10 years. Most studies focused on type 1 diabetes. Children with type 1 diabetes have a higher prevalence of CD (range from 5.5% to 20%), while the prevalence of CD in Down's syndrome patients was 1.1% and 10.7% in UAE and Saudi Arabia, respectively. Other autoimmune diseases associated with CD are thyroid disease and irritable bowel disease. The most widely recognized clinical presentation was an inability to flourish and poor weight gain, followed by short stature, abdominal pain, abdominal distension, bloating, and chronic diarrhea. Conclusion The prevalence of the celiac disease in Arab countries varies with sex and age. However, we found that celiac disease presented similar clinical characteristics independent of the geographic region. Longitudinal population-based studies are needed to better identify the true burden and determinants of celiac disease.


Introduction
Celiac disease (CD) is a chronic inflammatory disease of the upper small intestine triggered by gluten protein intolerance, which is prevalent in "genetically predisposed individuals." Gluten is the wheat grain protein richly consumed in Western countries with an average daily intake of 10 to 20 grams/person/day [1]. It is comprised of prolamin and glutelin proteins. Both proteins abundantly possess glutamine and proline residues, which defy gastrointestinal digestion and promote the deamination process through the tissue transglutaminase (tTG) enzyme [1,2]. It may lead to mucosal inflammation and villous atrophy, thus causing malabsorption [2]. The classical manifestation of CD is often present with all related signs and symptoms of malabsorption. Moreover, patients also experience diarrhea, steatorrhea, and loss of weight or growth failure [3]. Meanwhile, in children, the classical characteristics are diarrhea, failure to thrive, muscle wasting, poor appetite, abdominal distension, and sometimes emotional distress and lethargy [3].
The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) suggested diagnostic criteria for CD. According to the guidelines, it depends upon the gluten-dependent symptoms, CD-specific antibody levels, HLA-DQ2 and/or HLA-DQ8, and histopathologic findings, which are villous atrophy and crypt hyperplasia, in a biopsy of the duodenum [4].
Some epidemiological studies demonstrate that the prevalence of celiac disease has been undervalued, affecting not just Europeans but also the population of Mediterranean countries, including those in the Middle East [5,6], where its prevalence of celiac disease is quite similar to that of the Western states [7]. The incidence of celiac diseases in the Middle East is reported to be high both among at-risk groups and the general population. This is due to dietary habits such as excessive consumption of barley and wheat as well as due to a higher frequency of DR3-DQ2 haplotypes [8]. From a global perspective, the incidence of celiac disease differs from 1 : 132 in Switzerland to 1 : 1000 and 1 : 2000 in other European countries [9]. In the risk groups for celiac disease, a hereditary connection is present in first-degree relatives with a frequency of 1 : 22 and in relatives of a second degree with a frequency of 1 : 39 [10]. Celiac disease is also prevalent in the Nordic countries [11] with a frequency in the population, estimated by the results of serological screening of blood donors (in some cases supplemented with biopsy), of about 1/300 of that in the rest of Europe (especially that of Ireland and Italy) and around 1/250 of some areas of the United States [12]. In some regions, the prevalence of the celiac disease is 1/100. The disease develops in relatives of the first degree of relationship with a frequency of 10-20% [13]. The ratio of occurrence classified based on gender is 2 : 1 (females to males). Several studies have identified risk groups in which celiac disease is detected most often [13,14]. This group includes people suffering from other autoimmune and genetic diseases, including autoimmune thyroiditis, autoimmune liver disease, diabetes mellitus, Down's syndrome, and Turner syndrome, and relatives of celiac disease patients. The frequency of celiac disease in the risk groups can reach up to 10%. Therefore, an in-depth examination of patients with these diseases is recommended.
Several studies have been conducted about celiac disease in Arab countries; however, no recent epidemiological systematic review exists. We believed that ethnicity and geographical differences might affect disease frequency. Therefore, we carried out a systematic review to find the epi-demiology of CD in the Arab countries, and this includes the prevalence, associated risk factors, and clinical features.

Methods
This study used a systematic review research approach. To locate primary studies relevant to our review, a systematic and comprehensive search of multiple electronic databases, such as PubMed, Embase, and Google Scholar, was performed, with each database searched individually. The keywords based on Medical Subject Headings (MeSH) such as celiac disease, Arab countries, Saudi Arabia, epidemiology, prevalence, and Middle Eastern countries were systematically applied line by line and replicated in every source database using Boolean operators: (celiac or coeliac) AND (Algeria or Bahrain or Egypt or Iraq or Jordan or Kuwait or Lebanon or Libya or Morocco or Mauritania or Oman or Palestine or Qatar or Saudi Arabia or Somalia or Sudan or Syria or Tunisia or United Arab Emirates or Yemen) AND (epidemiology or risk or burden or prevalence or incidence or impact or prognosis). Complete local journal searching and crossreferencing were undertaken by two reviewers who agreed on the final selection of the articles.

Inclusion and Exclusion
Criteria. The inclusion criteria were original research studies published in peer-reviewed journals, mainly focusing on epidemiology, burden, prevalence, risk factors, incidence, or prognosis of celiac disease in Arab countries. Studies that utilized observational, retrospective, and prospective studies and were published in English between 1996 and 2019 were included. Studies that were published before 1996 focused on non-Arab populations, or enclosed case reports, case series, and quasiexperimental research designs were excluded from this review.

Study Selection.
The titles/abstracts of the search outcomes were studied, and when the suitability of the articles was in question, the full-text articles were demanded and evaluated. Based on the exclusion and inclusion criteria, relevant full-text articles were assessed, screened, and reviewed by two researchers for inclusion. Any disagreements between authors were resolved through discussion with the third author. This ensured that only the articles relevant to the research questions were included. In total, 134 research papers were retrieved. Of these, 35 were deemed suitable for analysis and relevant for inclusion into our documented review by both reviewers.
2.3. Data Analysis. All analyses and reviews on literature were conducted based on the PRISMA "(Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Relevant extracted papers were synthesized systematically. The collected data was summarized through narrative with an overview of geographical location, study design, study settings, populations, sample sizes, and case definition. It was then followed by synthesis of the selected studies based on the outcome measures. Due to the heterogeneity of the presented data, a meta-analysis was not possible. Figure 1 represents the article screening and retrieval process.

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BioMed Research International 2.4. Quality Assessment. The quality of the studies included in this review was assessed using the Newcastle-Ottawa Scale (NOS) [15]. The scoring scale of the modified NOS ranges between 0 and 8: low-quality studies with NOS scores 0-2, medium quality studies with NOS scores 3-5, and highquality studies with 6-8/9 NOS scores.

Results
Overall, 134 articles were reviewed and assessed for eligibility to meet our inclusion criteria. After individually reviewing each abstract against a prespecified inclusion criterion, 99 articles were excluded. This yielded 35 research articles, which focused primarily on the epidemiology of the celiac disease in Arab countries. The study selection process is summarized in Figure 1. We extracted articles from the period of 1996 to 2019. The studies included different research designs such as cross-sectional studies, prospective studies, casecontrol categorized under observational study design, and retrospective hospital-based studies with 22,340 participants from 12 Arab countries.
As seen in the following table, there were 35 published studies about celiac disease conducted in the Arab world. The national focus of these studies is divided in the following way: 17 were from Saudi Arabia, 1 from Algeria, 1 from Libya, 3 from Tunisia, 2 from Egypt, 2 from Oman, 2 from Jordan, 2 from the United Arab Emirates, 1 from Iraq, 1 from Kuwait, 1 from Qatar, 1 from Morocco, and 1 focused on the entire Middle East. The 22 studies focused on the prevalence, risk factors, and frequency of celiac disease among high-risk groups, and 9 focused on the prevalence of CD among the general population, while 4 of the 35 studies reported the clinical patterns and manifestation of CD. Not available in English, celiac disease epidemiology was not focused on, and focused on non-Arabs.

Studies included in synthesis (n = 35)
Full-text articles assessed for eligibility (n = 63) Figure 1: Retrieval of articles and screening process. BioMed Research International

Prevalence of CD among General Population.
The prevalence of CD in healthy adult populations was found to range from 0.14% to 3.2%, the highest (3.2%) prevalence being reported in Saudi Arabia and the lowest (0.14%) in Tunisia (see Table 2). In healthy children, the estimated prevalence ranged from 0.6% to 1.5%. Studies conducted in Saudi Arabia estimated the frequency of the disease to be 1 : 250-100. Approximately, the peak of diagnosis falls around the age of 1 to 3 years. Table 3 shows the clinical characteristics of laboratory-confirmed CD patients. The most widely recognized presentation was an inability to flourish and poor weight gain, followed by short stature, abdominal pain, abdominal distension, bloating, and chronic diarrhea.

Discussion
This review included 35 studies, showing a wide variation in the prevalence of CD, ranging from 0.14% to 3.2%. The highest prevalence among otherwise healthy individuals was reported in Saudi Arabia at 3.2%, and the lowest was in Tunisia at 0.14%. Gender distribution revealed a high occurrence in females. The peak age at diagnosis fell around the age of 1-3 years to 9-10 years. It was also found to be associated with type 1 diabetes in Saudi children in addition to thyroid dis-ease, Down syndrome, and irritable bowel disease. The most common symptoms were an inability to flourish, poor weight gain, short stature, chronic diarrhea, abdominal pain, gas, and bloating. Most of the studies used anti-tTG titers and EMA for their diagnosis. The role of family history was also highlighted in one study. Moreover, a gluten-free diet was found to improve laboratory parameters. However, noncompliance for this was also picked up by one of the studies. Several studies have indicated that CD is occurring with increasing prevalence in several geographic regions, particularly in the regions of European origin, indicating that it is generally a lifelong disorder [48]. It usually affects one in a hundred among the general population, being more prevalent in the Middle East and North Africa [13]. The literature demonstrated that the CD prevalence rates were 1% for the United States and Europe and were similar in Argentina and Australia [13]. Prevalence in North Africa has been reported as 0.79% in Libya, 0.6% in Tunisia, and 0.53% in Egypt. A regional study on the Greater Middle East showed a prevalence rate of 0.88% in Iran, while it was 0.6% in Turkey. Studies have shown prevalence in India to be 0.7% [49], whereas in Germany, it was 0.3%, 0.9% in Northern Ireland, 1.2% in Italy, and 2% in Finland [50]. However, in Saudi Arabia, it was between 2.1% and 8.5% [12], and not much statistical data were found on the frequency of CD due to the complexity of diagnosis, not only in adults but also in children.
Many of the studies included in this review concluded that CD occurred more frequently in females and particularly affected children more than adults. Likewise, its adult and  BioMed Research International childhood occurrence in Sweden was between 1 : 285 and 1: 77 [51], while it was 1 : 230 and 1 : 106 in Italian schoolaged kids [52]. Similar trends were also found in non-European peoples such as Australia [53,54], Argentina [54], Brazil [55], and New Zealand [56]. CD is a female predominant disease having a female to male ratio of 2 : 1 or 3 : 1 [57], which was congruent with the findings of this review. Ciacci et al. [58] established that women were diagnosed with CD at an early age, suffered more symptoms, had lower body mass index according to their age, and had severe anemia. According to Jane Anderson, up to 70% of individuals currently diagnosed with CD are female. This can be explained by two factors. Firstly, more women than men have it, and secondly, women seek medical care more often than males and hence get diagnosed more frequently if they have developed CD. Despite its increasing prevalence, the diagnosis rate is low. This could be due to poor disease awareness as well as limited diagnostic facilities in these countries. It can sometimes occur as an asymptomatic condition, yet the common gastrointestinal presentations in children include failure to thrive, chronic diarrhea, abdominal distention, and a malabsorptive picture including anorexia, vomiting, and constipation [59]. These symptoms were in line with those evaluated by the majority of the studies where the diagnosis was made only based on the clinical picture and laboratory parameters. Some studies in our review also highlighted the coexistence of CD with other metabolic conditions. Previously published data also supported this comorbidity pattern. From a study, 6% of type 1 diabetes patients while 12% of those with Down syndrome had CD in United States [60]. Along with many other conditions, autoimmune thyroiditis [61] and irritable bowel disease were associated with CD [62].
Most of the studies used anti-tTG titers and EMA for CD diagnosis while one study also showed that the patient underwent endoscopy if any one of the listed tests were positive. Moreover, the anti-tTG was shown to have high specificity and sensitivity in diagnosing CD, specifically in type 1 diabetic children. On a similar note, testing serum levels of anti-tTG was acknowledged as the first choice for CD screening, displaying approximately 98% sensitivity and up to 96% specificity [59]. Improvement of the condition after excluding foods based on gluten products showed improvement in both laboratory indicators and symptoms of the patients. This treatment was also found effective by many other studies [5,63].
The research review and analysis of this article contributes towards understanding the epidemiology and occurrence of CD in Saudi Arabia as well as other neighboring Middle Eastern and Gulf countries, providing a recent 9 BioMed Research International comprehensive overview of the topic. Variation in statistics between the studies can also be attributed to different methodologies and sensitivities of diagnostic tools. There were certain limitations to this review. First, Arabic papers were not included, yet most of the research conducted in Arab countries is published in English anyways. Another important limitation lies in the fact that cross-sectional data cannot be used to infer causality. Another major drawback is that we could not conduct a meta-analysis due to the heterogeneity of data.

Conclusion
With increasing prevalence, CD is becoming a major public health concern; thus, investigating its epidemiology and

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BioMed Research International clinical features is of great importance. It is now well known that gluten is a precipitating factor, and the research being conducted at present is adding to the understanding of other components of this condition. Awareness of the diversity of presenting symptoms has alerted health professionals to the possible diagnosis of celiac disease. Globally, many patients with celiac disease, including in Saudi Arabia and Gulf countries, remain undiagnosed, which may lead to the development of innovations in screening programs. A growing body of evidence reveals that there is an amplified possibility of celiac disease epidemics soon, especially in the Arab countries that practice gluten-rich dietary patterns. Since many of the cases remain underdiagnosed, the concerned authorities should endeavor to raise the responsiveness of celiac disease. There is a pressing need for research in the future to classify the exact prevalence of the celiac disease.

Implications.
Although only 1% of the overall general population has CD, evidence proposed that only around 10% to 15% of this population (children and adults) have been accordingly diagnosed and treated [64]. Hence, early CD diagnosis is crucial, as it might prevent complications. For this to happen, awareness is the key. Emphasis should be on effective communication between the patient and the physician to minimize the disease burden by screening for high-risk individuals. Additionally, periodic follow-up care of such patients is an essential element of effective longterm management of CD. There is a definite need for public health involvement by raising attentiveness towards CD and related dietary habits as well as early screening programs. Future studies in the Arab world should be further aimed at investigating the clinical features of celiac disease and shedding more light on its associated risk factors, preventive measures, early diagnosis, and appropriate treatment modalities.
Longitudinal population-based studies are needed in the future to better identify and respond to the burden and risk factors of celiac disease in Arab countries.

Conflicts of Interest
The authors declare that they have no competing interests.