Open access peer-reviewed chapter

Celiac Disease

Written By

Nour Amin Elsahoryi

Submitted: April 16th, 2021 Reviewed: April 22nd, 2021 Published: July 14th, 2021

DOI: 10.5772/intechopen.97834

From the Edited Volume

Inflammation in the 21st Century

Edited by Vijay Kumar, Alexandro Aguilera Salgado and Seyyed Shamsadin Athari

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Celiac disease is chronic autoimmune-mediated small intestinal enteropathy. CD caused by ingestion of the dietary gluten that found in wheat, barley, and rye, in the individual who are predisposed genetically by having leucocyte antigen, (HLA)-DQ2 or -DQ8-positive. Rigorous adherence to a gluten-free diet is the only treatment for this condition to reduce the symptoms and the consequences at the short-term and the long term. The aim of this chapter is provide updates and comprehensive overview about the celiac disease epidemiology, pathogenetic information, clinical, and diagnostic methods, updated therapeutic strategy approaches that followed as a treatment and recommendations. Its challenge to understand all the domains that causes celiac disease. Finding alternative diet and trying different lifestyle still under debates. However, complete exclusion of the gluten-containing food from the patient’s diet is the only effective treatment to avoid the disease complications.


  • Celiac Disease
  • Epidemiology
  • Pathophysiology
  • Genetics
  • Diagnosis
  • Risk Factors
  • Complications
  • Treatment

1. Introduction

In most studies and publications, coeliac disease or Celiac disease (CD) is characterized as a serological and histological immune-mediated disease caused by dietary gluten in people who are genetically predisposed to it [1, 2]. Individuals who have positive HLA-DQ2-positive and/or HLA-DQ8 and consume glute-contains diet are susceptible to have CD because they have genetic and/or environmental factors [1, 2]. Gluten is the storage protein of wheat and founds in the endosperm of other cereals (secalins in rye, hordeins in barley and avenins in oats [3]. The gluten protein is a CD trigger that could found also in that cereals hybrids such as the spelt, and the kamut [4]. This protein is composed of two main fractions: prolamin and glutelin in various proportions among the causative cereals. For example, the prolamin is about 68% and glutelin is 82% in the wheat, 52% and 71% in the rye and 62% and 71% in the barley, respectively [4]. However, the other proteins component such as albumins and the globulins are related to the IgE-mediated allergic response in the genetically susceptible individuals that have positive leukocyte antigen HLA-DQ2-and/or HLA-DQ8 [4].

The small intestinal is the primary affected organ with CD, intraepithelial lymphocytes (IELs) count increase after gluten ingestion and the immune response leads to structural changes in the gut such as villi blunting or flattening (villous atrophy) and elongation of the crypts (crypt hyperplasia) [2]. CD could lead to various extraintestinal symptoms and manifestations (Gastrointestinal and Extraintestinal) [2] as shown in Table 1, but also it is very important to mention that some patients remain asymptomatic.

Gastrointestinal manifestationsDiarrhea, loose stools, weight loss, dyspepsia, distended abdomen, flatulence, chronic abdominal pain, anorexia, vomiting, chronic constipation, and growth retardation (in children).
Extraintestinal manifestationsRecurring headaches, Epilepsy and seizures, Peripheral neuropathy, Cerebellar ataxia, Depression and Anxiety and Chronic fatigue, Short stature, delayed puberty, hepatitis, elevated liver, transaminases, iron-deficiency anemia.
Skeletal muscles: Arthralgia, osteopenia, bone fractures, osteopenia, and arthritis.
In the oral cavity: Dental enamel hypoplasia, recurrent aphthous
mouth ulceration.

Table 1.

The clinical gastrointestinal and extraintestinal manifestations.

A few decades ago, CD was hidden and underdiagnosed disease, but recently this disease was well-diagnosed sequencE by positive celiac-specific serologic tests and small intestinal biopsy specimens to ensure the true incidence and to find the true prevalence globally [5]. In 2012, Gujral et al. [6] mentioned that approximately 1% of the global prevalence is suffering from CD. Recent systematic review and meta-analysis (2018) published that the pooled global prevalence of CD was 0.7% (95% CI, 0.5%–0.9%) [5]. The seroprevalence of CD from 96 studies was 1.4% (1.1%–1.7%, 95 CI) at significant heterogeneity (97.5%). Whereas the pooled global prevalence that was confirmed by biopsy was 0.7% (0.5%–0.9%, 95%CI). The highest CD prevalence was in Europe and Oceania (0.8%), followed by Asia (0.6%), Africa (0.5%) and 0.4% in South America as shown in Figure 1. Prevalence among children was higher than adults (0.9% and 0.5%, respectively) higher among the females than males (0.6% and 0.4%, respectively) [5].

Figure 1.

The pooled prevalence of biopsy-confirmed CD worldwide [5].

To date, the only effective treatment for CD is a lifelong strict gluten-free diet, which lead to recovery of the mucosal damage recovery in the small intestine. Following restricted GFD improves the clinical symptoms and reduce the short and the long term complications that associated with CD [1, 2, 7, 8, 9, 10, 11].


2. Epidemiology

In the last decades, prevalence of CD was investigated in many countries by determining the new incidents in a specific time (cross-sectional studies mainly) [3]. According to some reports, CD prevalence has increased in some countries, such as the United States, where CD prevalence is estimated to be between 0.5 and 1 percent of the general population [3]. In Finland and Italy, however, the incidence was lower [1]. Overall, the CD prevalence was found through screening the general population which includes the serological tests. The difference in the diagnosis method led to inaccurate estimation of the prevalence and it remains greatly unrecognized [2, 12]. Numerous studies calculated the prevalence based on the positive serology test with duodenal biopsies to confirm the incident, whereas other studies diagnose the incident based on the positive serology test only [1, 2, 3, 12]. Although the differences in the CD diagnosis and cases reporting confirmation, the prevalence of CD incidents increases worldwide [1, 2, 3, 12]. Moreover, recent evidence pointed to increase the morbidity and mortality with CD [12, 13] and diminished the quality of life [12].

Recent systematic review and meta-analysis revealed that the worldwide CD seroprevalence is 1.4% based on positive IgA anti-TG2 test and/or test of anti-endomysial antibodies [5]. The pooled global prevalence based on the confirmation of the biopsy results CD was 0.7% with a different result among the countries. For example, the high prevalence was reported in Europe and Oceania (0.8%) compared with South America (0.4%), Africa (0.5%) and Asia (0.6%) [5]. The epidemiological studies of CD reported that the incidents among females are more than males and among children more than adults [2, 3, 5]. In addition, the prevalence among patients who have higher first-degree relatives is more [1]. Moreover, the prevalence of CD is higher among the patients who suffer from other chronic diseases such as diabetes Meletus type 1 (DMT1), Down syndrome, and IgA deficiency [1, 14]. Based on specific geographical areas, United States, Brazil, Italy and Russia have the highest prevalence (1.6–2.3%), but very rarely in some countries such as China, Indonesia, Pakistan and unknown in other countries such as Far East Asia and sub-Saharan Africa [2, 3]. In the Arab country, Ashraf El-Metwally et al. reported in a recent systematic review that the CD prevalence was varied and the highest estimation was in Saudi Arabia (3.2%) and the lowest prevalence was in Tunisia (0.1%) [8]. The results among the Arab population were in agreement with the other populations, the incidence was higher among females than males, among children more than adults, and it is associated with other chronic diseases mainly Down’s syndrome and DMT1 [8]. Finally, some studies reported that CD prevalence is less than 0.5% such as china but Scherf et al. consider the prevalence in such countries is underdiagnosis and the remaining cases need more investigation [3].


3. Risk factors of celiac disease (CD)

Pathogenesis of CD is identified predisposing the risk factors and it is includes genetic factors and environmental exposure to the gluten protein that stimulates the autoimmunity that cause the mucosal damage and villous atrophy [1, 2, 3, 6, 12]. CD is a unique autoimmune disease in that its key genetic elements (human leukocyte antigen (HLA)-DQ2 and HLA-DQ8), the autoantigen involved (tissue transglutaminase (tTG)). In the case of CD, there is an imbalance between T helper 1 and 2 cell responses. The genetic and environmental factors are both lead to impair the function of the intestine, inappropriate immune response, and an imbalanced gut microbiome [1, 2]. Overall, susceptibility to having CD is thought to be due to a combination of genetic and environmental factors as shown in Figure 2.

Figure 2.

Risk factors required for celiac disease development.

3.1 Genetic factor

In the heritability of CD, there is a relevant role between the incidence and HLA haplotypes class II heterodimers, specifically DQ2 and DQ8 by ~25–40% of the genetic risk. Lindfors et al. reported that class II is histocompatibility complex molecules stated on the antigen-presenting cells (APCs) surface; they consist of an α-chain and a β-chain encoded by specific variants of the HLA-DQA1 and HLA-DQB1 genes, respectively [2]. HLA-DQ2 is encoded by the HLADQA1*05:01 and HLADQB1*02:01 (also called HLA-DQ2.5) alleles, whereas HLA-DQ8 is encoded by the HLADQA1*03 and HLADQB1*03:02 alleles [2]. Most CD patients (around 90%) have positive-HLA-DQ2 and the rest of them carry HLA-DQ8 [2]. HLA-DQ2 homozygosis form a higher risk of the early appearance of the disease in the children within the first relatives [1] and the average prevalence of CD among the first degree is more than the general population. It’s important to mention that HLADQ2 and HLA-DQ8 are common among the general peoples (25–35%), and only 3% of this HLA compatible person have CD [1]. Most studies reported that the other HLA-DQ variants form a fairly modest risk effect (~15%) on CD because they are infrequently associated with this condition [1, 2, 12].

3.2 Environmental factor

Pro-autoimmune genetic background, viral infections not only the factors that could lead to the incident of CD [1, 2, 3, 12]. Ingestion gluten protein and early termination feeding practices are considered viral in CD development, autoimmunity, and then damage the mucosal tissue [1, 2, 3, 12]. Gluten is the storage protein in wheat that gives the dough viscoelastic properties [2]. Gluten is composed of alcohol-soluble constituents (gliadins) that consist of α-gliadins, γ-gliadinsand ω-gliadins, whereas the alcohol-insoluble glutenin consists of high-molecular-mass and low-molecular-mass glutenins [2]. Both segments (Gliadins and glutenins) are high in proline and glutamine amino acids which are resistant to proteolytic processing by gastric and pancreatic enzymes as well as mammalian small intestinal brush-border membrane enzymes [2]. Gluten is called CD trigger; it is a harmful dietary factor for CD patients, but to date, it is not clear why not all peoples who are genetically predisposed have CD and why some cases are diagnosed later in life [12]. The prevalence of CD is higher among the population that is characterized by higher consumption of wheat [12]. The recent epidemiological studies show the difference in the prevalence based on the region [12]. The effect of the environmental factor still varies among the studies. For example, three systematic reviews and meta-analysis [15, 16, 17] reported that is no association between timing of gluten introduction and CD and the age of the patient, whereas other studies reported conflicting data [18, 19]. Incomplete digestion of the gluten in the human gut led to producing the gluten peptide that accesses the lamina propria through the epithelial barrier via the transcellular or paracellular route. Among CD patients, gluten peptides activate both adaptive and innate immune responses [1, 2]. Small intestinal mucosal gluten specific CD4+ T cell is an immune response in CD patients in addition to producing antibodies towards wheat gliadin and the enzyme TG2 (encoded by TGM2). The amino acids that available in the gluten peptide at key positions are selectively deamidated by TG2 [2].

3.3 Feeding practice

Numerous studies indicated that CD is associated with feeding practice, time of gluten introduction to the infant (age of gluten intake) and the infant diet type [1, 2, 3, 6, 12]. Consuming gluten-containing food in the first three months of the infant age is significantly associated with CD autoantibodies development compared with the latest months [2, 12, 20]. On the other hand, recent meta-analyses reported that there is no association between CD and breastfeeding [15]. Regards the time of the gluten intake, large prospective studies show that no association between CD and gluten introduction time among the high-risk populations [17, 18]. One study reported that high gluten doses in the infancy stage associated with CD [19]. The results still contradictory in this regard and more research is required.

3.4 Infection

An increased risk of CD has been linked to repeated rotavirus infection in a previous longitudinal prospective study [21]. Therefore, a recently study reported that rotavirus vaccination could have a protective effect on developing CD [22]. Furthermore, early childhood infections with enterovirus A and B, especially those with a high titer and a long duration, were linked to later CD, while adenovirus infections were not. Surprisingly [3, 23]. The prevalence of acute respiratory infections seems to be a factor as well [3, 23].

3.5 Microorganisms

CD is like all autoimmune diseases, reducing the risk of microorganisms, decrease exposure to various microorganisms and increase the hygiene aspects which could be related to reducing the autoimmune disorders [1, 2, 12]. Many studies supported the abundance of specific bacterial types with CD patients such as Clostridium, Prevotellaand Actinomyces andspecific microbial virulence genes such as viruses, including rotavirus and reovirus [2, 12]. In addition, a recent study reported that infants who carrying a high-risk genotype characterized by a low number of Bifidobacterium; B. longus[24]. The presence of these microorganisms and changing their function lead to an increase the autoimmune and inflammatory diseases [12]. Therefore, a number of recent studies supported the role of these microorganisms in CD development as a secondary cause with remains the direct cause proved [2, 12]. On the other hand, some studies suggested that some microorganism such as Helicobacter pylorior cytomegalovirus) may delay CD development, but the mechanism still unknown [2]. Some epidemiological studies focused on modulating the intestinal microbiota but still, the evidence is limited [25]. Furthermore, smoking is another environmental factor that mentions in some old studies. Snook et al. mentioned that the prevalence of CD was higher among smokers [26]. Lower economic status as well as and it is worthy to mention under the risk factors of CD because it is the inferior hygienic environment [27]. Overall, explaining the development of CD requires deep and accurate evidence related to the patient’s characteristics, genetic and environmental factors together that is currently not fully understood.


4. Classification of variants of CD

4.1 Potential CD

Potential CD characterized by positive antibody (IgA EmA and anti-tTG) for CD with HLA-DQ2/HLA-DQ8, positive genetic markers, a normal intestinal mucosa, and few inflammation signs [28]. The intestinal mucosa in the potential CD is normal or inflamed slightly due to an increase in Els number [29]. Patients with potential CD could be asymptomatic or they may have extraintestinal symptoms [29]. Most children (80%) who suffer from the potential CD are asymptomatic and the other 20% have intestinal symptoms and extraintestinal signs such as delay in the anthropometrics [30, 31]. In CD adults, the symptomatic phenotype is common than in children and mostly extraintestinal symptoms [30, 31, 32]. Regarding the treatment, the current studies suggested that symptomatic potential patients only should follow GFD [30, 31, 32] . However, only a small percentage of patients with potential CD stick to the GFD and they suffer from villous atrophy [29, 30, 32]. The villous atrophy in the CD cases happen normally due to many causes as shown in Figure 3, but the restricted GFD reduce the probability of most causes and consequently reduce the small intestinal villi damage [33, 34].

Figure 3.

Causes of small intestinal villous atrophy.

4.2 Seronegative CD

A CD genetic test is also important because a negative outcome definitively rules out the disorder and leads doctors to look for other causes of villous atrophy. Morphology of the intestinal mucosal and serology testing is the basics tool for CD diagnosis [1]. The endoscopy is performed after the serological tests that including EmAs TG2-Ab assays [2]. The serological tests are very accurate and sensitive, its sensitivity arrived at (90–100%) and 100% specificity for coeliac CD [35]. EmA testing has long been considered the gold-standard tool for detecting the autoantibodies of CD [2]. On the other hand, the serological tests are considered a subjective test, indirect immunofluorescence, expensive and low throughput. Whereas the operator-independent enzyme is more common and operated on automated instruments by linking the immunosorbent assay (ELISA) and radio binding assay for TG2-Abs. the last method depends on the TG2 antigen quality, this means some of these tests could reveal negative and false-positive results negative and false-positive results. However, low TG2-Ab may be associated with other autoimmune diseases such as infectious disease and DMT1 [36]. Furthermore, approximately 10% of CD patients are seronegative, meaning they are undetectable by any of the existing serological methods [37]. After one year of GFD adherence, patients performed seronegative which assure improvement in the disease symptoms and the histology, because the diagnosis in the seronegative case depends on detection of small intestinal mucosa injury [37].


5. Diagnosis and screening of celiac disease (CD)

Currently, the clinically diagnosed cases are reported the epidemiological studies, but most research reported that there are heavily underestimated cases in every country [2]. In the high knowledge countries, the prevalence of CD is closer to the real estimation, whereas the other country still has the submerged CD iceberg. Working on increasing the diagnostic rate of CD is still a point of contention [3, 38, 39]. The current findings reported that there is growth in CD diagnosis. Mucosal changes detected by duodenal biopsy and serological test positivity (antitTG antibodies, anti-endomysium antibodies (EmA), and deamidated gliadin peptide (DGP) antibodies) are the gold standard, according to the most recently updated data. Intestinal biopsy is a critical assistant to assure a correct diagnosis because there is no antibody test that can provide perfect accuracy of sensitivity and specificity [1]. Commonly, the Pediatrics skipped the duodenal biopsy if they have high anti-tTG antibodies, positive EmA, HLA-DQ2/HLA-DQ8 and CD symptoms CD based on the recent recommendations of the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) [1, 40]. However, not all the world countries followed ESPGHAN recommendations such as the USA due to weakness in anti-tTG assays [41]. Despite this, duodenal biopsy remains an important part of the diagnosis of adult patients with suspected CD. The common clinical signs and symptoms of CD have evolved from childhood malabsorption symptoms to milder multi-organ manifestations that can occur in both childhood and adulthood [2, 12]. Loose stools, stomach pain, and flatulence are the most common signs, although in certain instances, no gastrointestinal disorders could be discovered [2]. In addition, there are some common clinical symptoms among CD patients. For instant, 10% of CD adults have Dermatitis herpetiformis and the iron deficiency anemia is also common [2, 8, 12, 42, 43]. Moreover, CD could be asymptomatic in specific cases for those who are screening with the high-risk group such as first-degree relative CD, DMT1 and down syndrome [2, 41, 42]. The current gold standard of care stated that four out of five of the following conditions are sufficient to diagnose CD [1, 45]: observe the typical signs and symptoms which include diarrhea and malabsorption; positive antibody test; positive HLA-DQ2 and/or HLA-DQ8, villous atrophy and damage in the intestine and clinical improvement resulted from following GFD. Most of these rules are used by the physicians to identify the other CD forms. Absence of intestinal damage point guides them to the potential CD, absence of the antibody positivity guids them to the seronegative CD, absence of the typical signs and symptoms guide them to a non-classic CD while absence of the response to GFD guide them to non-responsive CD [1].

5.1 Hematologic and blood biochemistry tests

CD could be suspectable by routine blood tests [46]. Low albumin, hemoglobin and micronutrients such as potassium, calcium, vitamin D and magnesium are associated with classical CD. Concerning iron and ferritin values, low ferritin and microcytic anemia values are very common among CD patients. Dimorphic anemia, macrocytic and non-macrocytic is not popular among patients with CD [47]. Numerous micronutrients deficiency was detected among CD that leads to important symptoms and diseases such as vitamin D3 deficiency that causes osteopenia and osteoporosis [48]. Even in the absence of other relevant symptoms, a cryptogenic increase in transaminases may signal the onset of CD. Transaminases return to normal range within 6–12 months after following a GFD [49]. Among the adults, Corazza et al. reported that the blood smear has the ability to identify changes in the membrane and cytoplasm of red blood cells, whereas, Nomarski phase contrast microscopy could detect the pitted red cells [50]. However, autoimmune diseases and their complications such as refractory CD, ulcerative jejunoileitis, and lymphoma are associated with macroscopically apparent or even functional hyposplenism, which is a predisposing factor for the development of infectious diseases caused by encapsulated bacteria such as Meningococcus and Pneumococcus [51].

5.2 Serology tests

A CD genetic test is also important because a negative outcome definitively rules out the disorder and leads doctors to look for other causes of villous atrophy [1]. Morphology of the intestinal mucosal and serology testing is the basics tool for CD diagnosis [1]. The endoscopy is performed after the serological tests that including EmAs TG2-Ab assays [2]. The serological tests are very accurate and sensitive, its sensitivity arrived at (90–100%) and 100% specificity for coeliac CD [35]. EmA testing has long been considered the gold-standard tool for detecting the autoantibodies of CD [2]. On the other hand, the serological tests are considered a subjective test, indirect immunofluorescence, expensive and low throughput. Whereas the operator-independent enzyme is more common and operated on automated instruments by linking the immunosorbent assay (ELISA) and radio binding assay for TG2-Abs. the last method depends on the TG2 antigen quality, this means some of these tests could reveal negative and false-positive results negative and false-positive results. However, low TG2-Ab may be associated with other autoimmune diseases such as infectious disease and DMT1 [36]. Furthermore, approximately 10% of CD patients are seronegative, meaning they are undetectable by any of the existing serological methods [37]. After one year of GFD adherence, patients performed seronegative which assure improvement in the disease symptoms and the histology, because the diagnosis in the seronegative case depends on detection of small intestinal mucosa injury [37].

The diagnosis of CD is not simple as its overlaps with different conditions of villous atrophy such as Giardia lamblia(parasitic infections), Crohn’s disease, autoimmune enteropathy, immunodeficiency, HIV enteropathy, tropical sprue, and Whipple disease [1, 52, 53]. However, CD patients with seronegative are associated more with autoimmune diseases compared with classical CD patients. This association the morbidity due to the late diagnosis of a specific condition [52]. Deamidated Gliadin Peptide (DGP) antibodies test is the recent test that suggested in the CD diagnosis for cases the not detected by the EmA and TG2-Ab tests, but this method is not popular in the clinical practice [54]. In addition, number of commercial point-of-care rapid tests are available currently. For anti-DGPs and TG2-Abs detection [55]. Although there is little data on the performance of rapid tests, they provide immediate results in a primary care setting and may be useful in resource-constrained settings [55].

5.3 Duodenal biopsy

The duodenal biopsy still a cornerstone in the Morphological evaluation in CD confirmation and Histology still the gold standard choice of CD diagnosis [52]. With the addition of mild villous atrophy and minimal lesions as potential expressions of gluten-related intestinal injury, the histological requirements for CD have drastically modified [56]. Currently, four biopsies on the second duodenal portion are recommended and additional two biopsies at the bulb [57]. Based on Marsh classification (modified by Oberhüber), the different types of lesions of the intestinal mucosa are classified into five stages. This classification is used as a reference for CD diagnosis in all CD centres [58]. Lesion’s types one and two described high IELs (with or without crypt hyperplasia) and standard villi. The potential CD is characterized by minimal intestinal lesions and positive anti-tTG and EmA. Moreover, this case (minimal intestinal lesions) is consistent with other causes such as allergies of some types of food as cow milk proteins, Crohn’s disease, lymphocytic colitis. In lymphocytic enteritis, IEL cytometric pattern is more precise than subepithelial deposits of anti-TG2 IgA for CD diagnosis [59]. For CD patients, the recent evidence approved that the normal cut-off of IEL is ≥25 lymphocytes over 100 epithelial cells. The typical lesion (type 3) of CD demonstrates villous atrophy with a change in the villi-to-crypt ratio and an increase in IEL. Type three lesions are divided into three subdivided based on the severity of the atrophy as following: 3a means mild atrophy, 3b means partial atrophy, 3c means subtotal atrophy [58]. The diagnostic algorithm for CD diagnosis was illustrated by [1] in Figures 4 and 5.

Figure 4.

The diagnostic algorithm for celiac disease diagnosis. Figure source [1].

Figure 5.

The diagnostic algorithm for seronegative villous atrophy. Figure source [1].


6. Complications and consequences of CD

Most evidence suggests that having a late diagnosis of CD and/or not adhering to a strict GFD increase the mortality rate than the general population [60]. The most common complications of CD among elderly patients include Hyposplenism, Refractory CD, Hyposplenism and ulcerative jejunoileitis [1]. Around 30% of the CD adults have hyposplenism and it is associated with bacterial infections and other autoimmune diseases [61]. The refractory CD is associated with malabsorption, BMI reduction and diarrhea but it is from a small percentage of the CD cases (around 1–1.5%). Refractory CD is classified into two categories (type 1 and type 2). However, both categories are depending on the symptoms, improvement level and the CD patients response after following GFD [62]. Commonly the diagnosis of refractory CD takes place after one year of GFD by the negative serology tests [62].

Furthermore, the CD is correlated with malabsorption which resulted from villous atrophy [2]. Nutrition malabsorption leads to multiple deficiencies in the macronutrients such as the calories and micronutrients such as the vitamins and the minerals deficiencies [63, 64]. Following the GFD, on the other hand, was linked to adverse effects such as improvements in food delivery, insufficient fortification of gluten-free foods items, and individual dietary habits. The most common nutritional consequences of CD include Iron deficiency, Vitamin B12 deficiency, Vitamin D & calcium deficiencies, Folic acid deficiency, micronutrient and mineral deficiencies [63, 64]. All these nutrients deficiencies are linked with the traditional symptoms as diarrhea and BMI fluctuation [2]. Few studies have been assessed the nutritional value of the GFD, but most studies concluded that GFD has an imbalance of nutrients and could be associated with vitamins and minerals deficiencies such as calcium and vitamin and non-starch polysaccharides [2, 63, 64]. Therefore, the ideal treatment contains balanced GFD and the nutrients deficiencies should be diagnosed and treated by dietary supplement intake [63, 64].


7. Celiac disease (CD) prevention and management

7.1 Prevention

Inconsistent results were published regarding the prevention intervention for CD. The old study suggested starting early feeding wheat during breastfeeding to the infant [65]. In contrast, other intervention and cohort studies concluded that early wheat feeding practice did not prevent CD [3, 17]. Moreover, a number of systematic reviews and meta-analyses were approved that the infant practice such as duration of the breastfeeding not associated with CD prevention [15, 66]. Another Swedish cohort data reported that increasing the gluten consumption above five grams daily during the first two years is associated with an increase in the risk of CD among the study population [67]. From another side of view, some studies link intestinal infection and increase the CD risk factor [27, 68]. Therefore, the association between CD prevention effect and the environmental practice still needs further evaluation. Overall, the primary strategies of CD are the early and the correct diagnosis by screening diagnosis or by case finding [2]. Whereas secondary prevention reducing the symptom and the complications by following the recommended treatment [3, 17].

7.2 CD management

To date, the only effective treatment for CD is consuming gluten-free food such as fruit, vegetables, legumes, and gluten-free cereals. According to Codex Alimentarius (Codex Standard 118-1979) the recommended amount of gluten for CD patients does not exceed 20 mg/kg of gluten [69]. The researchers now are trying to improve the quality of gluten-free products by developing new analysis methods for gluten detection [3]. The safety of the gluten-free diet is an important aspect for CD patients because the contaminated products could have an illegal amount of gluten. In addition, the tolerable level varies among the CD patients.

The compliance rate of CD patients to the GFD is very poor. In general, children have more adherence to the GFD than adults because they are diagnosed in early childhood [3]. Patients compliance is affected by the age, gender, socioeconomic status of the patients [70]. Many studies were conducted on the CD patients compliance to the GFD to improve adherence [70, 71, 72, 73]. However, some of these studies result was based on the symptoms diagnosis after following GFD and other studies used Anti-TG2 serology test to check the compliance rate. In general, the antibody titers decrease gradually after following a strict GFD, sometimes it takes a longer time in the case if it was high at diagnosis [70]. However, the best test is performing duodenal biopsies to check the compliance and the adherence of the CD patients. Comino et al. reported that detection of the gluten immunogenic peptides (GIP) in patient’s feces urine was used as a biomarker for the patients gluten intake and consequently to the GFD adherence [74]. However, the last method is non-invasive as duodenal biopsies and it is relatively simple but it has weakness point in the relation of the antibody levels and with the dietary assessment questionnaires [74].

Following GFD is the only treatment to date and efficacious for most patients but following strict GFD is not easy. On the other hand, Most CD patients prefer any non-dietary treatments like vaccination, supplements, or medications [75].

Therefore, studies are making a great effort to find alternative treatments for CD patients [12]. A number of studies reported the availability of proteolytic enzymes (glutenases) of microbial or plant origins that could degrade gluten proteins quickly in similar conditions to the human stomach (low pH). These glutenases enzymes are promising drugs to eliminate the immunogenic capacity of dietary gluten due to their effectiveness in cleaving proline-and glutamine-rich gluten sequences [76, 77, 78]. Vitro and pre-clinical studies indicated that the glutenase leads to reduce the number of gluten epitopes in wheat-containing food [76, 77, 78]. Bethune believes that using glutenases as an oral enzymatic therapy for CD is a good idea [79]. These enzymes can be produced by the germination of wheat and it could be used to eliminate residual gluten from the food, but it is not enough to use as oral supplements [80]. Alternative treatment for CD patients is still being researched in vitro and in vivo, either as an add-on therapy to the GFD, as a rescue therapy after accidental gluten exposure, or as a substitute for the GFD [3].


8. Gluten-free diet (GFD)

The recommended and the documented treatment for CD patients, to date, is lifelong strict adherence to GFD [3, 8, 9, 44, 81, 82, 83]. Catassi et al. revealed that consuming 50 mg of gluten for three months could destroy the small intestine [84]. However, there is no documented recommended dose for the threshold dose for CD especially for the children [12]. While good adherence to the GFD leads to better intestinal healing and consequently improves the symptoms compared with patients who consumed gluten-contaminated food [12]. Using GFD led to avoid the gluten peptide sources located in the wheat, rye, barley and all cross-breeds of these cereals [85]. Wheat varieties such as kamut, einkorn, spelt also should be avoided because it is derived from wheat and many cereals are still in debate because it is contaminated by the wheat as oat [12]. However, wheat is the main component of the main food items such as bread and pasta. In addition, it is used in food processing as a thickening and stabilizing agent. Therefore, it exists in many food products. Following GFD leads to improve the symptoms which are considered as the first key sign of GFD adherence [86]. In addition, the small intestinal histology assessment and the inflammation tests, serology tests and dietary history assessment are the clinical checkpoints that are used to confirm the GFD adherence [87]. However, patients who are following GFD notes improvements in all the previous symptoms. Furthermore, some studies reported that following restricted GFD among CD patients is associated positively with the intelligence and education level [88]. In contrast, untreated patients and poor adherence to the GFD could lead to intestinal mucosa destruction and consequently suffer from nutrients deficiencies such as iron-deficiency anemia, malnutrition, malabsorption such as calcium and vitamin D, bone disorders [64]. Improvement the symptoms, malabsorption adjustment and health status recovery could be observed gradually after following GFD [89]. On the other hand, following GFD is a common trend worldwide as some peoples consider omitting wheat from the diet to support the health status [90]. Furthermore, patients with gluten intolerance that caused or Non-celiac gluten sensitivity follow GFD without proof of CD [91].

WHO codex [92] FDA define the gluten-free term in (2013) that food contains <20 parts per million (ppm) of gluten which equivalent to 20 mg of gluten per kg of food [12]. The starch of gluten contains little amounts of residual gluten, therefore, most factories nowadays are trying to purify the starch based on the standard to meet the Codex requirements in the US [12]. In other countries such as Australia and New Zealand, the guidelines are different. The rule is zero gluten in gluten-free food [12]. Currently, the most common analysis method to measuring the gluten in the food is R5 ELISA (Mendez) [93]. Despite the current use of this assay, it is not accurate to detect the contaminated product such as the oats and the barely as they contain different -molecular-weight peptides unlike that found in the wheat [94]. Therefore, improve more accurate analysis methods to detect the gluten in the food is still under enhancement [12].

Overall, following GFD is the ideal treatment for CD patients, but this diet includes a number of considerations as it contains a high amount of carbohydrates and a lower amount of fibers compared to the normal diet [12]. The ideal GFD should include balanced nutrients besides deity supplements if needed in the case of the nutrients deficiencies [63, 64]. The nutrient recommendations (based on age and gender) revealed that the carbohydrates should cover 55% of total calories with adequate dietary fiber (20–35 g daily). Around 25–30% or less of the total caloric should come from the monounsaturated and polyunsaturated fatty acids. In addition, five servings of fruit or vegetables daily at least are also recommended [63, 64].


9. Follow-up CD patients

Consult a dietitian is strongly recommended for CD patients after confirming the diagnosis [63, 64]. The dietitian can help the patient how to balance the GFD to improve the symptoms through six main principles that have been recommended for CD patients by NIH guidelines [95]. As well as follow of the CD patients is very important to confirm the patent’s adherence to GFD and to check the consequences and the complications [2]. Analysis of the serum antibodies used to detect the GFD although other tests such as serological testing are also recommended [2]. The only reliable tool now is repeating the biopsy during the GFD but it is challenging [96].


10. Conclusions

Based on the most recent research, the prevalence of CD is increasing over time CD and it is starting to become emerge in some countries such as Africa and Asia. Many factors were suggested by a large number of studies that include mainly; Genetic predisposition, exposure to gluten, loss of intestinal barrier function, a pro-inflammatory innate immune response triggered by gluten; inappropriate adaptive immune response is the main reason for CD. The imbalanced gut microbiome has an indirect cause that could enhance disease development. Economic status and smoking are considered as other risk factors that could be related to CD. To date, there is still a gap in the scientific evidence regards the relationship between all the suggested factors that could lead to the CD. Therefore, more data should be collected to estimate the prevalence of CD in the world. In addition, further research is needed to identify the factors that influence the progression of CD autoimmunity to mucosal damage, as well as the biomarkers that predict this progression, so that preventive measures and non-dietary treatments can be developed. Following GFD is the effective treatment until now. Raise awareness level of CD regards the early diagnostic, effective diet, and other related issues are the most appropriate policy to be implemented to improve the diagnostic rate of CD.

11. Recommendations

  • Biopsy remains the main and the essential tool for CD diagnosis and the serology cannot substitute for biopsy in the diagnosis of adult CD.

  • When a patient is on a GFD, a duodenal biopsy is needed, as well as positive serology in the vast majority of adult patients.

  • Patients should adhere to a GFD and have an intake of less than 10 mg gluten per day and the aim of the follow-up is to ensure strict adherence to the GFD.

  • At the time of diagnosis, patients may begin eating gluten-free oats.

  • In patients with CD, a GFD is advised to reduce the risk of adverse foetal outcome and lymphoma.

  • When adherence is challenged, patients with CD should be followed up by a dietitian and/or clinician with an experience or expertise in this area.

  • Patients with symptoms should be evaluated more closely than those with no symptoms.

  • Patients should be encouraged to join their local coeliac support group as soon as they are diagnosed.

  • Duodenal biopsy should be considered in people who have an upper endoscopy and have laboratory tests, signs, or endoscopic features that indicate CD.

  • To rule out CD, HLA typing should be used. A positive DQ2.5 or DQ8 result will never be enough to validate the diagnosis.

  • Individuals who are self-treating on a GFD who have never had adequate CD testing before changing their diet can use HLA typing.

  • In high-risk individuals with CD, such as first-degree kin, HLA typing may be used to rule out CD and reduce potential testing.

  • The diagnosis of CD requires duodenal biopsy when the patient is on a gluten-containing diet and for the vast majority of adult patients also positive serology.

  • Duodenal biopsy should be retained as the mainstay for the diagnosis of adult CD and cannot be replaced by serology.

  • If CD is suspected during endoscopy, at least four biopsy specimens, including a duodenal bulb biopsy, should be collected.

  • A duodenal biopsy should be considered in serologically negative patients who exhibit symptoms of malabsorption (such as anemia or diarrhea) or have a family history of CD.

  • Follow-up biopsies may be considered in patients with CD and are potentially helpful in identifying patients at increased risk of lymphoma.

  • Follow-up biopsies are not mandatory if the patient with CD is asymptomatic on a GFD and has no other features that suggest an increased risk of complications.

  • Follow-up biopsies should be undertaken in patients with CD whose condition does not respond to a GFD.

  • Although there is insufficient evidence to suggest community screening for CD, according to National Institute for Health and Care Excellence recommendations, there should be a low threshold for case finding in clinical practice.

  • CD tests should be done on symptomatic first-degree relatives of CD patients.

  • Patients that have additional risk factors for osteoporosis or who are over the age of 55 should have a Pneumococcus vaccine.

  • Bone density should be assessed after 1 year of diet in patients that have additional risk factors for osteoporosis or who are over the age of 55.

  • Adult patients with CD should have a calcium intake of at least 1000 mg per day.

  • Patients can have annual hematological and biochemical profiles, and a GFD is the mainstay of CD patients’ osteoporosis prevention plan.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations


Celiac Disease.


Diabetes Meletus Type 1.


The enzyme-linked immunosorbent assay.


Gluten Free Diet.


Intraepithelial Lymphocytes.


World Healthcare Organization.


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Written By

Nour Amin Elsahoryi

Submitted: April 16th, 2021 Reviewed: April 22nd, 2021 Published: July 14th, 2021