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Celiac Disease: Fallacies and Facts

Silvester, Jocelyn A. MD, PhD1,2; Therrien, Amelie MD, MS1; Kelly, Ciaran P. MD1

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The American Journal of Gastroenterology: June 2021 - Volume 116 - Issue 6 - p 1148-1155
doi: 10.14309/ajg.0000000000001218
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Our conception of celiac disease has expanded and become more sophisticated in concert with the tools available for its investigation (such as tissue transglutaminase [TTG] antibodies, deamidated gliadin peptides antibodies, HLA typing, and videocapsule endoscopy). Along the way, we have learned (and relearned) that celiac disease is different from the disease we thought we knew. In 1950s, celiac disease was exclusively considered a pediatric disease, and North American adults with steatorrhea and malabsorption were diagnosed with “nontropical sprue” and treated with a diet poor in fat and residue but rich in proteins and simple carbohydrates, sometimes in combination with oral steroids (1). Over the turn of the century, we found new insights about global prevalence and atypical clinical presentations including obesity. Moreover, other gluten-responsive conditions, such as nonceliac gluten wheat sensitivity and irritable bowel syndrome (IBS) have been identified. Contrary to conventional wisdom, there are severe limitations to a gluten-free diet (GFD) as an effective treatment for celiac disease. No medication is as yet approved for celiac disease, but many opportunities for nondietary treatments are under active study. This commentary is a summary of an invited presentation by Ciaran P. Kelly at the American College of Gastroenterology 2019 Annual Meeting. After writing this article, we learned of a previous publication on celiac myths by Erica Boettcher and Sheila Crowe in 2014 (2), and we acknowledge their previous work on the topic.


The earliest record of celiac disease is attributed to Aretaeus of Cappadochia who described a chronic malabsorption syndrome in the second century. Although the role of diet was recognized by both American (Sydney Haas) and British (Samuel Gee) physicians, it was the observations of Wilhelm Dicke of the effects of rationing on Dutch children with celiac disease during the Second World War that led to identification of the toxicity of the gliadin fraction of wheat (2). Throughout most of the twentieth century, celiac disease was believed to affect primarily Europeans and those of European descent. Diagnosis was based on clinical suspicion and, later, small intestinal histology. Identification of serum antibodies associated with celiac disease and TTG as the target antigen facilitated development of noninvasive serologic tests and wide-spread screening (3). Epidemiologic data are now available for every continent except Antarctica. Our meta-analysis of these data revealed that although there is some geographic variation, celiac disease is remarkably ubiquitous. Globally, the pooled seroprevalence of celiac disease is 1.4% (95% CI 1.1%–1.7%), and the prevalence of biopsy-confirmed celiac disease is 0.7% (95% CI 0.5%–0.9%) (Figure 1) (4). A study in the United States found that the ethnic group with the highest prevalence of villous atrophy suggestive of celiac disease is not of European origin but from Punjab (3.08% vs 1.8% overall in North America) (5).

Figure 1.
Figure 1.:
Worldwide seroprevalence of celiac disease. Adapted from ref. 5 with permission from Elsevier (4,62–64).

Less is known about the prevalence of celiac disease in Africa. The seroprevalence in North African countries such as Morocco, Algeria, and Tunisia is similar to the rest of the world (1.1%), with also similar rates of HLA DQ2 and DQ8 haplotypes carriers in the Moroccan population (6). Studies unrelated to celiac disease found lower prevalence of DQ2 (11%) and DQ8 (6%) in Cameroon, Congo, and Gabon (6), allowing us to hypothesize that celiac disease may be less prevalent in these populations. We anecdotally know that celiac disease may occur in Ethiopians, sometimes with a delayed presentation considering the staple diet that is naturally gluten free. In South Africa, an observational study of children with T1D revealed a prevalence of biopsy-confirmed celiac disease of 2.5% (7). Epidemiologic data are also scant in parts of Asia. Most data are from Israel, Turkey, Iran, India, Jordan, Saudi Arabia, and Malaysia (8). Interestingly, there is considerable variation in the rate of HLA DQ2 carrier frequency among Asian countries, ranging from 0.3% in Japan (9), less than 5% in Korea and Indonesia, 5%–20% in China, Mongolia, Singapore, Taiwan, Thailand, and Vietnam to >20% in Australia, Pakistan, Israel, and Iran (10). By contrast, HLA DQ8 carrier frequency in Japan (8%–10%) was similar to the Western World (11). As such, estimates of seroprevalence of celiac disease among asymptomatic Japanese populations are low, ranging from 0.05% to 0.19% (12,13). Epidemiologic data are also particularly scant in China, where there could be some geographical/ethnic variations within the country. A study examining rural areas from Northern China showed a seroprevalence of 1.27% with a HLA DQ2 carrier frequency similar to Western populations (14).

Although genetic susceptibility, particularly the rate of homozygosity for HLA DQ2.5, influences the prevalence of CeD in a population, other environmental factors, such as the type of staple diet (15), enteric pathogens (16), and antibiotic use (17), are also important. This is exemplified by the striking difference in the prevalence of celiac disease in the Finnish and Russian areas of Karelia whose populations share similar genetic background, but different lifestyle (18).


Paradoxically, many patients with celiac disease are overweight or obese. Classically, children who developed celiac disease shortly after weaning presented with malnutrition secondary to malabsorption that was rapidly reversed by gluten withdrawal. Serologic testing facilitated the recognition that less dramatic presentations are common and many may be “asymptomatic.” In the Western World, it is estimated that between 15 and 31% of individuals with celiac disease are overweight at the time of the diagnosis and 6.8%–13% are obese (19–22). In one US cohort, 5% of children were obese at diagnosis (23). By contrast, most patients among a cohort in India were either underweight or normal weight at the time of celiac disease diagnosis, with only 6.2% being overweight and 2.9% obese (24). Among a cohort of 679 adults with celiac disease who we followed for a mean of 39.5 months, one-third had a high body mass index (BMI) at diagnosis (21% overweight plus 12% obese) (25). Overall, BMI increased significantly on a GFD (mean 24.0–24.6, P < 0.001), and 22% of those with a normal or high BMI at diagnosis increased their BMI substantially (by >2 points). The degree of BMI increase was proportionate to GFD duration suggesting that weight maintenance counselling is an important aspect of celiac disease follow-up care and dietary education (26). Others have reported that BMI may decrease on a GFD for some overweight or obese individuals (19,22). This may relate to individual food choices as processed and manufactured gluten-free foods tend to be higher in calories and fat than naturally gluten-free alternatives.


TTG IgA antibodies are the recommended initial screening test for celiac disease in all age groups (26,27). Because these tests, and the earlier anti-gliadin IgA and anti-endomysial (EMA) IgA tests, were used clinically, it was quickly recognized that they may fail to detect celiac disease in those who are IgA deficient (28). Thus, it is recommended that negative serum TTG IgA testing be followed by determination of total serum IgA. In those who are IgA deficient, TTG IgG and EMA IgG seem to have a similar sensitivity and specificity to TTG IgA-based tests in those who are IgA sufficient (28–30). Notably, selective IgA deficiency (total serum IgA <0.07 g/L) is relatively rare compared with partial IgA deficiency (total serum IgA <2 SDs below the mean for age). When we evaluated 1,000 consecutive patients screened for CeD at our center, TTG IgA was highly sensitive (100%) for CeD in those with partial IgA deficiency (31). Similar findings have been reported in children (32).


For many years, the importance of improving and increasing diagnosis of celiac disease has been emphasized. Now, because the population with diagnosed celiac disease who are following a GFD expands, it is apparent that many individuals with celiac disease do not respond to a GFD. Greater than 15% of adults have persistent or frequent symptoms despite an apparently strict GFD, also called “nonresponsive celiac disease” (NRCD) (33). It is important to evaluate these patients because although gluten ingestion is the most common cause of NRCD, it is not the only cause, and some causes call for very different management approaches, such as microscopic colitis, other food intolerances, small intestinal bacterial overgrowth, and IBS (Figure 2). Relatively few (0.04%–1.5%) have refractory celiac disease, which is defined as persisting symptoms and villous atrophy, despite a GFD (34,35). However, other conditions may still be associated with persisting villous atrophy, including hidden gluten exposure, small intestinal bacterial overgrowth, autoimmune enteropathy, or common variable immunodeficiency. Other factors associated with symptomatic persistent villous atrophy include age greater than 70 years and use of proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or selective serotonin reuptake inhibitors (36).

Figure 2.
Figure 2.:
Diagnostic algorithm for NRCD. 1. Confirm the diagnosis of celiac disease by reviewing findings from serologic tests (not antigliadin antibody tests) and small bowel histology findings. If patients tested negative for tTG and EMA antibodies, perform HLA DQ2 DQ8 typing. 2. Investigate other possible etiologies for clinical presentation and/or abnormal histology findings. 3. Increased serum levels of IgA against tTG indicate continued gluten ingestion as a cause. 4. Nonceliac villous atrophy can be caused by intestinal infections (eg, giardiasis, small intestinal bacterial overgrowth, and viral enteritis, including human immunodeficiency virus enteropathy), autoimmune enteropathy, hypogammaglobulinemia, and combined variable immunodeficiency, tropical sprue, Crohn's disease, peptic duodenitis, or collagenous sprue. 5. Conditions that present as NRCD without villous atrophy include IBS, microscopic colitis, food intolerances, small intestinal bacterial overgrowth, Crohn's disease, and microscopic colitis. 6. Aberrant small intestinal mucosal and intraepithelial lymphocytes in patients with RCD type II can be identified by immunohistochemistry or flow cytometry (an excess of CD3+ cells without CD4 or CD8 surface proteins) or by T-cell receptor gene rearrangement analysis showing clonal expansion. Reprinted from ref. 66, with permission from Elsevier. IBS, irritable bowel syndrome; NRCD, nonresponsive celiac disease.

Moreover, mucosal recovery on a GFD is also not universal among those who respond clinically. Overall, only 1/3 of adults have normal villous architecture (a healthy, healed intestine) after 2 years on a GFD and 2/3 after 5 years on a GFD (36,37). This is only based on evaluation of the duodenum, so the proportion of celiac disease patients achieving complete mucosal recovery of the entire small intestine remains unknown. Nevertheless, the rate of persistent villous atrophy decreases with time on the GFD, so most individuals with celiac disease may eventually have mucosal recovery (38). Diagnosis during childhood and less severe histologic damage at diagnosis have been associated with mucosal recovery (39).


An increasing number of individuals adopt a gluten-free or gluten-reduced diet for multiple reasons. Some feel relief of gastrointestinal or extraintestinal symptoms, either because they have nonceliac gluten sensitivity (NCGS) or IBS (often with fructan intolerance and not an intolerance to all gluten-containing grains) (40–42). Others avoid gluten as part of a fad that is maintained by some athletes and public figures. It was estimated in 2012 that although at least 2 million people were following a GFD in the United States, only 300,000 (15%) actually had celiac disease (43). Nevertheless, a recent analysis of the NHANES cohort showed that although the prevalence of people avoiding gluten is increasing in the United States, the prevalence of diagnosed celiac disease on a GFD is also increasing (from 0.1% in 2009–2010 to 0.4% in 2013–2014). However, in 2013–2014, there were still 0.28% with undiagnosed celiac disease, whereas at least 1.7% of the population were avoiding gluten without a diagnosis of celiac disease (44).


One consequence of increased awareness of GFD is that self-treatment with a GFD before medical consultation is increasingly common. Serologic and histologic findings of celiac disease normalize on a GFD, making subsequent diagnosis more challenging. Moreover, IBS and so-called NCGS may respond to a GFD (40,42).

Differentiating between celiac disease and other conditions is clinically important because only celiac disease requires a lifelong strict GFD, carries risk for significant health complications, and is associated with a risk of disease in children and other relatives. By some definitions, elevated TTG IgA excludes NCGS. The conventional diagnosis protocol for NCGS includes following a regular gluten-containing diet for at least 6 weeks, followed by a GFD for at least 6 weeks. Responders should have a subsequent gluten challenge, preferably as a cross-over with a placebo challenge (45). This methodology has identified some individuals with gluten sensitivity among populations with IBS and functional dyspepsia (46,47). Interestingly, in a recent randomized double-blind placebo-controlled cross-over study involving challenges with gluten, fructans, and placebo, fructans were associated with significantly higher symptoms scores than gluten in this patient population (40).

Among those in our clinic with a clinical response to a GFD who were evaluated for celiac disease, ever having TTG IgA or DGP IgG/IgA >2× upper limit of normal was associated with a positive likelihood ratio of celiac disease of 130 (95% CI 18.5–918.3) (48). Those with celiac disease were also significantly more likely to have a nutrient deficiency, another autoimmune condition, or a family history of celiac disease (Figure 3 and Table 1). HLADQ2/DQ8 genotyping may be useful when there is diagnostic uncertainty, such as when the patient is already on a GFD, there is villous atrophy with normal serology, or to assess whether relatives are at risk (34). The negative predictive value of HLA-DQ2/DQ8 is very high (∼99%); however, the positive predictive value is much lower (49). Thus, for the 40% of the population who are HLADQ2 and/or DQ8 carriers, prolonged gluten challenge remains the clinical tool of choice to confirm (or exclude) celiac disease (26,34).

Figure 3.
Figure 3.:
Serological and histological characteristics of individuals with response to a GFD. Reproduced with permission from Wolters Kluwer Health (ref. 49). CD, celiac disease; GFD, gluten-free diet; NCE, non-celiac enteropathy; NCGS, non-celiac gluten sensitivity; ULN, upper limit of normal.
Table 1.
Table 1.:
Clinical and demographic differences between celiac disease and NCGS


Notwithstanding persistent symptoms and ongoing villous atrophy, a GFD is an imperfect therapy, and the treatment burden is high. Among patients at our hospital, following a GFD for treatment of celiac disease was reportedly more burdensome than treatments for type 1 diabetes, IBS, inflammatory bowel disease, and congestive heart failure. Those with end-stage renal disease on hemodialysis were the only group to report a higher treatment burden than those with celiac disease (50). A strict GFD is difficult to maintain, particularly when eating food prepared by others outside the home, such as in restaurants or cafeterias, when travelling, or at social events. Groups who particularly struggle with a GFD include the elderly, the illiterate, those with mental or psychological impairment, and those with limited financial means. Naturally gluten-free grains may have gluten-containing grains introduced during planting, harvesting, or processing (51). Food preparation details also matter. Dusting meat with flour before grilling, using stock to cook rice, or steaming vegetables in the pasta water is not disclosed on menus. Gluten may also be found in some vitamins and supplements and products not intended for consumption such as glues, lipsticks, and play-doh.


Adhering to an absolutely strict 100% GFD is a tremendous challenge; thus, our patients often ask whether a less strict diet is sufficient. Catassi et al. (52) attempted to answer this question in a double-blind microchallenge study. Patients with biopsy-confirmed celiac disease who had normal duodenal villous architecture after being on a strict GFD for 2 years or longer were randomized to take 10 mg gluten, 50 mg gluten, or cornstarch placebo daily for 3 months while maintaining their usual strict GFD. The 50 mg daily gluten exposure was a low dose roughly equivalent to one fortieth of a slice of bread. Villous height crypt depth ratio (Vh:Cd) was similar in all 3 groups at baseline; however, there was a significant decrease in Vh:Cd in the 50-mg group after 3 months compared with placebo. Importantly, individual sensitivity is likely highly variable. One subject in the 10 mg group dropped out of the study after a month when they exhibited signs of relapse (vomiting, diarrhea, and abdominal distension). The investigators included a run-in period because some individuals participating in a research study may suddenly become more strict with their GFD, and this could bias the effects observed from the intervention; nevertheless, 19/39 participants (including 2 in the 50-mg group) had an increase/improvement in their Vh:Cd over the course of the trial. To put the amount of gluten involved into perspective, a regular diet is about 5–15 g of gluten/day in the Western World, which is at least 100 times the amount of gluten that is considered harmful (53). A previous study among children compared the effects of a daily intake of 100 mg and 500 mg of gluten. Both group had a worsening of the Vh:Cd and frequencies of IELs, except for one child in the 100 mg group who had a slight improvement of the Vh:Cd ratio (54). These studies are difficult to perform because they are necessarily conducted on a background of a “gluten-free” diet that contains low levels of gluten (see below). On the other end, recent studies using gluten immunogenic peptides tests in urine and stools still detect gluten exposures among those with Marsh 0-1 histology (55–57). It is fair to conclude that individual responses to gluten exposure are highly variable, but a chronic gluten exposure of at least 50 mg for more than a month will likely induce intestinal damage.


In a survey of adults diagnosed with celiac disease in England, 40% reported intentional gluten exposure within the past 6 months and an additional 30% reported unintentional gluten exposure during the same period (58). Recently, our group completed the Determination of Gluten Grams Ingested and Excreted By Adults eating Gluten-free (DOGGIEBAG) study (57). Eighteen adults with biopsy-confirmed celiac disease who had been on a GFD for 24 months collected food (25% portions in a “doggie bag”), urine, and stool samples over a 10-day period. Although no intentional gluten exposures were reported, two-thirds had at least one sample that tested positive for gluten immunogenic peptides. Eliminating all dietary gluten may be an aspirational goal that is difficult to attain even for highly motivated patients. This has been implicitly acknowledged for years because the definition of “gluten free” is not absolute but allows for 20 parts per million gluten in foods.


All guidelines for management of celiac disease recommend lifelong adherence to a strict GFD. However, as previously mentioned, the treatment burden is high on a GFD, and it is an imperfect treatment for celiac disease (Table 2). As such, this condition is poised for drug development, being a commonly encountered disorder needing a lifelong therapy, with many steps in celiac disease pathogenesis being well elucidated. Surveys suggest that most patients with celiac disease would be interested in a medical therapy (59). The potential target celiac disease populations have also evolved, indications for therapies being initially as adjuncts to the GFD for people with RCD or NRCD. We are now aiming for the ultimate goal—to achieve “tolerance” to allow those with celiac disease to consume gluten safely—either in small amounts or ultimately in the amounts found in a normal diet. Examples of therapeutic agents in the pipeline include glutenases (latiglutenase NCT03585478, TAK062 NCT03701555), tight junction regulator (larazotide NCT03569007), and nanoparticles inducing tolerance to gliadin (TAK-101 NCT04530123, KAN-101 NCT04248855).

Table 2.
Table 2.:
Fifty Years of Real-World Clinical Experience With a GFD

As with many other conditions, diagnosis of celiac disease is limited by our not remembering to include it as a diagnostic consideration. Failure to consider celiac disease continues to be a common contributor to diagnostic delays (60,61). Celiac disease has been reported in every continent except Antarctica, although epidemiologic data are still missing in several African and Asian countries (4). It does present among individuals who are overweight and obese, and the effects of the GFD on body habitus are variable (22). Differentiating celiac disease from NCGS is also crucial because the importance to adhere to a strict for celiac disease patients is currently essential, but very burdensome (50). For many, symptoms persist, involuntary exposures are frequent (57), and mucosal recovery is not universal (36). Inducing tolerance to gluten in celiac disease could be a “game changer” not only for patients with celiac disease but also for other autoimmune disorders with less well-defined disease pathogenesis and antigenic triggers.


Guarantor of the article: Ciaran P. Kelly, MD.

Specific author contributions: Conception and design: J.A.S., and C.P.K.. Drafting of the manuscript: J.A.S., A.T., and C.P.K. All authors have approved the final draft submitted.

Financial support: Research reported in this publication was supported by the National Institute of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number K23 DK119584. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Potential competing interests: Not related to current work; C.P.K. has acted as a scientific advisor to companies attempting to develop new diagnostic and management approaches for Celiac disease including Cour Pharma, Glutenostics, Innovate, ImmunogenX, Takeda, Johnson & Johnson, Kanyos, Merck. He also acts as Principal Investigator on a research projects on Celiac disease supported by Aptalis and Merck. J.A.S. has received consulting fees from Takeda Pharmaceuticals International Co, and research support from Cour Pharmaceuticals, Biomedal SL and Glutenostics LLC. She was supported by the National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number K23 DK119584. A.T. was supported by Douglas G Kinnear Award from the Association des Gastroenterologues du Quebec and FRQS Phase II award for clinician-scientist training.


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