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Celiac Disease Review | OMICS International
ISSN: 2161-069X
Journal of Gastrointestinal & Digestive System

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Celiac Disease Review

Sandeep Nijhawan* and Gopal Goyal

Department of Gastroenterology, Sawai Man Singh Medical College, J L N Marg, Jaipur, 302 004, India

*Corresponding Author:
Sandeep Nijhawan
Department of Gastroenterology
Sawai Man Singh Medical College
J L N Marg, Jaipur
302 004, India

Received date: September 29, 2015 Accepted date: October 26, 2015, Published date: November 04, 2015

Citation: Nijhawan S, Goyal G (2015) Celiac Disease Review. J Gastrointest Dig Syst 5:350. doi:10.4172/2161-069X.1000350

Copyright: © 2015 Nijhawan S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Gastrointestinal & Digestive System


Celiac disease (CD) is a systemic, immune-mediated disorder that primarily affect small intestine and triggered by dietary gluten in genetically susceptible individuals. Gluten is a water insoluble protein complex, which is found in wheat, rye and barley. A significant finding of celiac disease is villous atrophy of small intestine which leads to nutrient malabsorption and broad range of clinical manifestations.


Celiac disease; Epidemiology


Celiac disease (CD) is a systemic, immune-mediated disorder that primarily affect small intestine and triggered by dietary gluten in genetically susceptible individuals. Gluten is a water insoluble protein complex which is found in wheat, rye and barley. A significant finding of celiac disease is villous atrophy of small intestine which leads to nutrient malabsorption and broad range of clinical manifestations [1].

A recent International Consensus has defined three categories of adverse effects caused by wheat ingestion: (1) the autoimmune reaction classified as CD, dermatitis herpetiformis (DH) and gluten ataxia (2) allergic reactions and (3) non-celiac gluten sensitivity (NCGS) [2].


Prevalence of celiac disease is approximately 0.6 to 1.0% worldwide, with wide regional differences [3]. The highest prevalence rate of the disease is noted in the Saharawi people of Africa in whom celiac disease prevalence is believed to be around 5% [4]. A recent multinational study in Europe found a big differences in CD prevalence with the lowest prevalence (0.3%) in Germany and the highest in Finland (2.4%) [5]. The frequency of celiac disease is increasing in many developing countries also. India has CD predominance in northern part of country where the prevalence is around 1.04% [6].

CD is prevalent in the first-degree relatives of patients with CD and it has been found to be 4.8% [7]. Book et al and Farre et al observed that the siblings (7.2%) are more affected than the parents (1.8%) [8,9].

Genetic background plays a key role in the predisposition to the disease. Majority (90%) of celiac disease patients express HLA-DQ2 haplotype (DQA1 0501/DQB1 0201). Another 5% of patients express HLA-DQ8 haplotype (DQA1 0301/DQB1 0302) [10]. Children with HLA haplotype DR3-DQ2 homozygote are at higher risk for celiac disease especially early in childhood by the age of 5 years [11].

The infants with family risk of developing CD with HLA-DQ2 haplotype influence the early gut microbiota composition and associated with intestinal dysbiosis and may contribute to determining disease risk [12]. Most patients are carriers of the HLA-DQ2/DQ8 genes but these genes are also present in about 40% of the general population, and only a small percentage (2-5%) develops CD [13,14] this indicate that the HLA-DQ genotype is necessary but not solely responsible for the development of the disease.

Clinical Presentation

Celiac disease is now being recognized as a systemic disease that may affect persons of any age, races and ethnic groups [15].

Traditionally the subtypes of the disease include typical, atypical, latent, silent and potential CD. The “typical” form is characterized by signs and symptoms caused by enteropathy and the consequent GI malabsorption, including diarrhea, weight loss, steatorrhoea and hypoalbuminemia. The “atypical” form does not present with weight loss and diarrhea but the clinical manifestation can nevertheless involve the GI, liver or organs other than the GI skin, nervous system, bones, metabolism, and reproductive system.

Oslo definitions discourage the term “silent” CD because it is equivalent to asymptomatic CD. They suggest instead, classifying as “subclinical CD” the forms that are below the threshold of clinical detection and whose signs and symptoms are not sufficient to fall within the CD diagnostic algorithm [16]. The Oslo definitions highlight the confusion regarding the term “latent” CD, and discourage its use. Instead, they recommend using the term “potential” CD for individuals without intestinal damage who are at increased risk of developing the disease as indicated by the presence of CD autoantibodies

Clinical presentation of celiac disease varies greatly according to age group. Paediatric patients of CD present more often with typical features than adult patients. A study has shown that diarrhoea is the presenting symptom in 74% of children as compared to 58.7% of adolescent/adults [17]. More than half of adult patients with celiac disease present with atypical manifestations [18]. Other manifestations of CD are chronic fatigue, aphthous stomatitis, short stature and reduced bone mineral density [1]. Celiac disease patients also have some nutritional deficiencies including iron, vitamin D, folate, vitamin B12, vitamin B6 and zinc [19]. Iron deficiency has been reported in up to half of newly diagnosed adults and in itself is an indication for screening [20].

CD patients who present with anaemia are more likely to have severe villous atrophy and a low bone mass density than patients who present with diarrhoea at the time of diagnosis [21]. Unusual manifestations of celiac disease include dermatitis herpetiformis, gluten ataxia and celiac crisis, a rare life-threatening syndrome mostly observed in children [1]. Neurological disorders like peripheral neuropathy, seizure disorders, ataxia and impaired cognitive function most often have been described in adults with CD at a lower incidence than in children [22,23]. In CD, hypertransaminasemia is often a subclinical finding. Rarely CD can be associated with severe liver disease also [24].

Increased Risk of other Diseases

Individuals with CD are at increased risk of non-alcoholic fatty liver disease (NAFLD) compared to the general population, excess risk is highest in the first year after CD diagnosis but persist throughout 15 years after the diagnosis of celiac disease [25]. Patients with celiac disease have an almost 3-fold increase in risk of developing pancreatitis [26].

Autoimmune thyroid disease and type I diabetes mellitus are the most common autoimmune diseases that occur with celiac disease. People with CD have 2.4-fold increased risk for type I diabetes mellitus before they are 20 years old [27]. CD is observed in approximately 7% of patients with autoimmune thyroid disorders [28]. Associations with Sjögren syndrome, Addison’s disease, parathyroid disorders, and growth hormone deficiency also have been reported [29].

CD affects approximately 2.5% of cirrhotic patients [30]. A study has shown that liver diseases are most commonly associated with CD [31]. Irritable bowel syndrome (IBS)-type symptoms occur frequently in patients with CD and are more common than general population. The pooled prevalence of IBS-type symptoms in all patients with CD is 38.0% [32]. CD is associated with small intestinal bacterial overgrowth (SIBO). In a study, it has been shown that large number of celiac patients from North India suffers from bacterial overgrowth (20.7%) which can be accordingly treated with antibiotics [33].

Celiac disease with pregnancy

Undiagnosed celiac disease during pregnancy has been associated with adverse outcomes. Many patients with celiac disease have malabsorption, weight loss, and anaemia. A nationwide study found that there is an increased risk for malformations among the offspring of mothers or fathers with celiac disease. However, the excess risk is small [34].

Non celiac gluten sensitivity (NCGS)

Present with symptoms which are often indistinguishable from CD. NCGS is characterized by intestinal and extra intestinal symptoms that occur soon after gluten ingestion, disappear during a gluten-free diet and relapse when the diet is interrupted. The main gastrointestinal symptoms are bloating, abdominal pain, diarrhea, and constipation. The extra intestinal symptoms include eczema, skin rashes, muscle and joint pains, leg or arm numbness, headache, “foggy mind” a sense of fatigue and depression. Several studies have suggested a link between gluten intakes and neuropsychiatric disorders particularly autism and schizophrenia [35].

NCGS patients are distinguishable from CD by serology and biopsy as they are negative for more specific markers of CD such as tTG, EMA, and anti-DGP [36]. The prevalence of HLA-DQ2-DQ8 is about 50%, more than the 30% found in the general population but considerably below the prevalence among celiac patients. Intestinal biopsy is negative for CD in patients with NCGS. The mucosa appears without graded histological lesions, usually Marsh 0 or Marsh 1 type. A diagnosis of non-celiac gluten sensitivity should be considered only after CD has been excluded with appropriate testing [37]. An approach to diagnosis of NCGS and its differentiation from CD after appropriate testing has shown in Figure 1 [38].


Figure 1: Diagnostic model for symptoms responsive to gluten exclusion. CD: Celiac Disease; NCE: Non-Celiac Enteropathy; NCGS: Non-Celiac Gluten Sensitivity; ULN: Upper Limit of Normal.

Complication of Celiac Disease

Complications associated with untreated celiac disease include osteoporosis, impaired splenic function, neurologic disorders, infertility or recurrent abortion, ulcerative jejunoileitis and carcinomas [39].

Celiac disease with malignancy

Patients with CD have an increased risk of cancer in comparison to general population. Increased risk of malignancy is seen in oesophageal adenocarcinoma, small intestinal adenocarcinoma, non- Hodgkin's lymphoma and melanoma. Adenocarcinoma of the small intestine is rare but this risk is increased many folds in patients with celiac disease but overall risk is very low. The non-Hodgkin's lymphoma includes both T-cell and B-cell types and occur in both gastrointestinal and extraintestinal sites. The risk of non-Hodgkin's lymphoma persisted despite a gluten-free diet [40]. Most lymphomas complicating celiac disease are indeed related to the disease and are not of the enteropathy-type T-cell lymphoma (ETTL) [41].

The most common type is diffuse large B-cell lymphoma and carrying a better prognosis than T-cell lymphoma. Therapy is unsatisfactory for enteropathy-type T-cell lymphoma [42].

Diagnosis of celiac disease: The confirmation of a diagnosis of CD should be based on a combination of findings from the medical history, physical examination, serology and histological analysis of multiple biopsies of the duodenum.

Serology: Serological tests are fundamental for CD screening. Immunoglobulin A (IgA) anti-tissue transglutaminase (anti-tTG) antibody is the preferred single test in individuals over the age of 2 years who do not have concomitant IgA deficiency [43]. The sensitivity and specificity of various serological tests are shown in Table 1 [44,45].

Test Sensitivity (Range) Percent Specificity (Range) Comments
IgA anti-tTG antibodies >95.0 (73.9-100) >95.0 (77.8-100) Recommended as first level screening test
IgG anti-tTG antibodies Widely variable (12.6-99.3) Widely variable (86.3-100) Useful in patients with IgA deficiency
IgA antiendomysial antibodies >90.0 (82.6-100) 98.2 (94.7-100) Useful in patients with an uncertain diagnosis
IgG DGP >90.0 (80.1-98.6) >90.0 (86.0-96.9) Useful in patients with IgA deficiency and young children
91.0 (82.6-97.0) 54.0 (12.0-68.0) High negative predictive value

Table 1: Various serum tests for diagnosis of celiac disease.

The sensitivity of serologic testing is markedly reduced in patients with a gluten-restricted diet, therefore patients should not restrict their diet before testing.

In persons with IgA deficiency, IgG anti-tTG antibodies can be measured. Measurement of deamidated gliadin peptide antibodies of the IgG class (IgG DGP), as an alternative test has better sensitivity and specificity than measurement of IgG anti-tTG antibodies [46].

Small intestinal biopsy: Upper GI endoscopy with multiple biopsies of the duodenum (one or two biopsies of the bulb and at least four biopsies of the distal duodenum) are ecommended to confirm the diagnosis [47]. In a study it has been shown that villous atrophy may be present only in the duodenal bulb [48-50]. The characteristic histologic changes include an increased number of intraepithelial lymphocytes (>25 per 100 enterocytes), elongation of the crypts and partial to total villous atrophy [51].

However lymphocytic infiltration also known as lymphocytic duodenosis is common in the general population (prevalence of 5.4%) [52]. Diagnosis of CD requires the demonstration of histological changes associated with the disease which can be classified according to Marsh, Marsh modified (Oberhuber), or the more recent simplified Corazza classification which are shown in Table 2 [53-55].

Marsh modified (Oberhuber)  Histologic criterion Corazza
Increased intraepithelial lymphocytesa Crypt hyperplasia Villous atrophy
Type0 No No No None
Type1 Yes No No Grade A
Type2 Yes Yes No  
Type3a Yes Yes Yes(partial) Grade B1
Type3b Yes Yes Yes(subtotal)  
Type3c Yes Yes Yes(total) Grade B2

Table 2: Summary of histologic classification frequently used for celiac disease, a >40 intraepithelial lymphocytes per 100 enterocytes for Marsh modified (Oberhuber); >25 intraepithelial lymphocytes per 100 enterocytes for Corazza.

Lymphocytic infiltration of the intestinal epithelium in the absence of villous atrophy is not specific for CD and other causes should also be considered [51] (Figure 2).


Figure 2: Causes of villous atrophy other than celiac disease.

In patients with an uncertain diagnosis such as patients with negative serology and positive results on biopsy, detection of sub epithelial anti-tTG IgA deposits by means of double immunofluorescencemay be useful [56].

Biopsy of the small intestine may not be required in children with typical symptoms, a high titre of anti-tTG IgA antibodies (higher than 10 times the upper limit of the normal range) and predisposing HLA genotypes [44].

Ancillary testing in CD: HLA-DQ2/DQ8 testing should not be used routinely in the initial diagnosis of CD. It should be used to effectively rule out the disease in selected clinical situations examples: Equivocal small-bowel histological finding (Marsh I-II) in seronegative patients, evaluation of patients on a GFD in whom no testing for CD was done before GFD, patients with discrepant celiac-specific serology and histology, patients with suspicion of refractory CD where the original diagnosis of celiac remains in question and in patients with Down’s syndrome [47,57]. Capsule endoscopy should be considered for the evaluation of small-bowel mucosa in patients with complicated CD [58,59].

Intestinal permeability tests, D-xylose, and small-bowel followthrough are neither specific nor sensitive and are not recommended for CD diagnosis [47]. Considering the entire diagnostic test, following is the recommended algorithm for the diagnosis of celiac disease [47] (Figure 3).


Figure 3: Celiac disease (CD) diagnostic testing algorithm. DGP, deamidated gliadin peptide; HLA, human leukocyte antigen; Ig, immunoglobulin; TTGA, tissue transglutaminase antibody.

Screening of celiac disease: Screening of CD Should be considered in patients with symptoms, signs or laboratory evidence suggestive of malabsorption. Patient with a first-degree family member who has a confirmed diagnosis of CD and showing possible signs or symptoms or laboratory evidence of CD. Celiac disease should be sought among the explanations for elevated serum aminotransferase levels when no other etiology is found. Patients with Type I diabetes mellitus (DM) should be tested for CD if they have any digestive symptoms and signs or laboratory evidence suggestive of CD [47].

Diagnosis or exclusion of celiac disease in patients already on GFD: In this group of patients diagnosis begins with serologic tests and HLA typing. Positive results from serologic tests support a diagnosis of CD and indicate the need for duodenal biopsy analysis; conversely celiac disease is excluded for patients who are negative for HLA DQ2/ HLADQ8.

Gluten Challenge: Gluten challenge remains the gold standard for CD diagnosis in HLA-DQ2 or -DQ8-positive patients who have normal serologic and histologic findings when tested on a GFD. It must be noted that patients who develop severe symptoms following gluten ingestion are not suitable candidates for gluten challenge. Although gluten challenge with a diet containing at least 10 g of gluten per day for 6-8 weeks has long been the norm, there are few data to indicate the diagnostic efficacy of this approach or the optimum dose or duration of challenge.

A recent study found that even if a patient can only tolerate lower doses of gluten (3 g per day), diagnostic changes are seen in most CD patients after as little as 2 weeks of gluten ingestion [47]. An approach to gluten challenge for diagnosis or exclusion of celiac disease in patients maintained on gluten free diet has shown in Figure 4 [47].


Figure 4: An approach to gluten challenge for diagnosis or exclusion of celiac disease in patients maintained on gluten free diet.

Treatment of Celiac Disease

Treatment of CD involves a gluten free diet (i.e., a diet with no wheat, rye, or barley proteins) for lifelong. Although no gluten consumption is the ideal treatment for CD, a minimal degree of gluten contamination is difficult to avoid. The term “gluten free” indicates a diet that contains gluten at such a low level as to be considered harmless. The current international Codex Alimentarius defines gluten-free foods as having less than 20 ppm of gluten [1] the diet requires continuous education of patients and their families by both doctors and dieticians. A GFD will result in resolution of symptoms and repair of the intestinal damage over time in most people with CD. There is some evidence that people with untreated CD are more frequently deficient in a number of micronutrients compared to those without CD. Micronutrient deficiencies identified include iron, folic acid, and vitamin B12 and B6, copper, zinc and carnitine [60-64]. Low bone mineral density in people with untreated CD is believed to be partly due to vitamin D deficiency. Recommended gluten free diet has shown in Table 3 [51].

Grains that should be avoided
Wheat (includes spelt, kamut, semolina, triticale), rye, barley (including malt)
Safe grains (gluten-free)
Rice, amaranth, buckwheat, corn, millet, quinoa, sorghum, teff (an Ethiopian cereal grain), oats
Sources of gluten-free starches that can be used as flour alternatives
Cereal grains: amaranth, buckwheat, corn (polenta), millet, quinoa, sorghum, teff, rice (white, brown, wild, basmati, jasmine), montina (Indian rice grass)
Tubers: arrow root, jicama, taro, potato, tapioca (cassava, manioc, yucca)
Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts, Soybeans
Nuts: almonds, walnuts, chestnuts, hazelnuts, cashews
Seeds: sunflower, flax, pumpkin

Table 3: Fundamentals of the Gluten free diet.

New Advances in Celiac Disease Treatment

Newer Strategies include developing agents to degrade or alter dietary gluten, prevent gluten peptides from crossing the epithelial barrier, inhibit tTG-induced potentiation of gliadin peptides or block gliadin binding to HLA-DQ2. Immune-based strategies involve preventing T-cell activation or innate and adaptive immune responses [65]. However only 2 agents are in late phase 2 clinical trials.

ALV003 (2 recombinant, orally administered, gluten-specific proteases) is given orally, reduce the small intestinal mucosal injury caused by 6 weeks of gluten challenge [66]. Larazotide acetate, an oral peptide that modulates intestinal tight junctions, reduce symptoms in patients who are symptomatic despite a GFD [67,68].

Additional studies are underway to determine if these agents are safe and effective for patients with persistent symptoms and mucosal injury despite a continued GFD. These or other effective therapies could reduce the burden of GFD by decreasing the effects of inadvertent gluten exposure.

Monitoring of celiac disease: CD is a lifelong inflammatory condition that affects multiple organ systems, so patients should be followed up routinely. Serologic testing should be done every 3-6 months until normal and then every 1-2 years. Nutritional evaluation for iron, vitamin B12, folate etc. should be done every 3-6 months until it becomes normal. Low bone mineral density is one of the more common extraintestinal manifestations of celiac disease, so dualenergy x-ray absorptiometry (DXA) evaluation generally is recommended in the first year after diagnosis. Thyroid functions monitoring should be done first at diagnosis and then in every 1-2 years [69].

The optimal timing of the follow-up biopsy is unclear as all celiac disease patients do not reach mucosal recovery in 1 year time despite strict gluten-free diet. In patients with high dietary adherence, incomplete villous recovery after 1 year does not affect the clinical response or long-term prognosis so personalized approach is required to decide the optimal timing of the follow-up biopsy [70].

Non responsive celiac disease (NRCD)

NRCD may be defined as persistent symptoms, signs or laboratory abnormalities typical of CD despite 6-12 months of dietary gluten avoidance. NRCD is common, affecting from 7 to 30% of patients treated with a GFD for CD [71-73]. There are many distinct etiologies including inadvertent gluten ingestion (the most common cause), other food intolerances (including lactose and fructose intolerance), small-intestinal bacterial overgrowth, microscopic colitis, pancreatic insufficiency, irritable bowel syndrome and refractory CD [71-75].

Thus careful evaluation is needed to identify and treat the specific source in any given patient.

The first step in evaluation is to re-confirm the initial diagnosis of CD by review of small-intestinal histology and serology obtained at the time of diagnosis [47].

Refractory Celiac Disease (RCD)

It may be defined as persistent or recurrent symptoms and signs of malabsorption with small-intestinal villous atrophy despite a strict GFD for more than 12 months and in the absence of other disorders including overt lymphoma. RCD is uncommon, affecting 1-2% of patients with CD [76]. Refractory celiac disease can be classified as type 1 (normal intraepithelial lymphocytes) or type 2 (abnormal intraepithelial lymphocytes; clonal intra epithelial lymphocytes lacking surface markers CD3, CD8, and T-cell receptors; or both). Type 2 RCD is associated with a higher risk of ulcerative jejunoileitis and lymphoma than type 1 and associated with a significantly less favourable prognosis as compared to Type I RCD [77].

Management of Type I RCD includes strict gluten free diet, nutritional support and in severe cases steroid therapy is required [78] in patients with an incomplete response to steroid treatment immunosuppressive agents such as azathioprine may be beneficial but should be used with caution, since they may promote the progression to lymphoma [79]. Management of Type II RCD is difficult because they are less likely respond to therapy. Treatment options include systemic corticosteroids, enteric-coated budesonide, azathioprine, alemtuzumab (anti-CD52 monoclonal antibody) infliximab or cladribine (2-chlorodeoxyadenosine) [80-82]. Transformation to enteropathy-associated T-cell lymphoma (EATCL) is a prominent risk and may require treatment by surgery, chemotherapy, or bone marrow transplantation. In some patients EATCL may run a prolonged, nonaggressive course but the overall prognosis remains poor [83,84].

Collagenous Sprue: It is characterized by deposition of collagen under the intestinal epithelial cells and associated with persistent diarrhea, progressive weight loss and severe malabsorption causing multiple nutrient deficiencies [85]. It has been noted in up to 36% of patients with classic celiac disease. Complications of celiac disease have been described in collagenous sprue, including small bowel ulceration and free perforation as well as both T cell and B cell lymphomas [86-89]. Collagenous sprue should be considered in the differential diagnosis of NRCD and must be distinguished from collagenous colitis (which rarely accompanies celiac disease).


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