Summary Our knowledge of the pathophysiology of celiac disease has progressed enormously over the past 25 years; However, some fallacies regarding clinical characteristics and management persist. Global epidemiological data are now available showing that celiac disease is ubiquitous. A high body mass index is common at the time of diagnosis. The gluten-free diet (GFD) is an imperfect treatment for celiac disease; Not all people show a response. This diet is widely used by people without celiac disease, and symptomatic improvement in a GFD is not sufficient for diagnosis. Finally, GFD is burdensome, difficult to achieve, and therefore has incomplete efficacy, opening up exciting opportunities for novel non-dietary treatments. |
Our conception of celiac disease has expanded and become more sophisticated along with the tools available for its investigation (such as tissue transglutaminase [TTG] antibodies, deamidated gliadin peptide antibodies, HLA typing, and video capsule endoscopy).
Along the way, we have learned (and relearned) that celiac disease is different from the disease we thought we knew. In the 1950s, celiac disease was considered exclusively a pediatric disease, and North American adults with steatorrhea and malabsorption were diagnosed with "nontropical sprue" and treated with a diet low in fat and waste but high in protein and simple carbohydrates, sometimes in combination with oral foods. steroids. During the turn of the century, we found new insights into the global prevalence and atypical clinical presentations, including obesity.
Additionally, other conditions that respond to gluten have been identified, such as non-celiac gluten-free wheat sensitivity and irritable bowel syndrome (IBS). Contrary to conventional wisdom, there are serious limitations to a gluten-free diet (GFD) as an effective treatment for celiac disease. No medications have yet been approved for celiac disease, but many non-dietary treatment opportunities are being actively studied.
FALLACY #1: Celiac disease occurs primarily in Europeans and their descendants
The oldest record of celiac disease is attributed to Aretaeus of Cappadocia, who described a chronic malabsorption syndrome in the 2nd century. Although the role of diet was recognized by American (Sydney Haas) and British (Samuel Gee) doctors, it was Wilhelm Dicke’s observations on the effects of rationing on Dutch children with celiac disease during World War II that led to the Identification of the toxicity of the wheat gliadin fraction. Throughout most of the 20th century, celiac disease was believed to primarily affect Europeans and European descendants.
The diagnosis was based on clinical suspicion and, subsequently, on small intestine histology. The identification of serum antibodies associated with celiac disease and TTG as a target antigen facilitated the development of non-invasive serological tests and widespread screening.
Epidemiological data are now available for all continents 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% to 1.7%) and the prevalence of biopsy-confirmed celiac disease is 0.7% ( 95% CI: 0.5% to 0.9%).
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 of Punjab (3.08% vs. 1.8% overall in North America)
Although genetic susceptibility, particularly the homozygosity rate for HLA DQ2.5, influences the prevalence of ECE in a population, other environmental factors, such as the type of staple diet, enteric pathogens, and antibiotic use, are also important. . This is exemplified by the notable difference in the prevalence of celiac disease in the Finnish and Russian areas of Karelia, whose populations share similar genetic backgrounds, but different lifestyles.
FALLACY #2: People with celiac disease are not obese
Paradoxically, many patients with celiac disease are overweight or obese . Classically, children who developed celiac disease shortly after weaning had malnutrition secondary to malabsorption that was quickly reversed by gluten withdrawal. Serologic testing facilitated 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 people with celiac disease are overweight at the time of diagnosis and between 6.8 and 13% are obese. In a US cohort, 5% of children were obese at diagnosis. In contrast, most patients in a cohort in India were underweight or normal weight at the time of celiac disease diagnosis, with only 6.2% being overweight and 2.9% obese.
Among a cohort of 679 adults with celiac disease that we followed for an average of 39.5 months, one-third had a high body mass index (BMI) at diagnosis (21% overweight plus 12% obese). Overall, BMI increased significantly on a GFD (mean 24.0-24.6, P < 0.001), and 22% of those who had a normal or high BMI at diagnosis increased their BMI substantially (in > 2 points). The degree of BMI increase was proportional to the duration of GFD, suggesting that weight maintenance counseling is an important aspect of celiac disease follow-up care and dietary education.
Others have reported that BMI may decrease on a gluten-free diet for some overweight or obese people. This may be related to individual food choices, as processed and manufactured gluten-free foods tend to have more calories and fat than naturally gluten-free alternatives.
FALLACY #3: Serum TTG-IgA tests are not useful for diagnosing or excluding celiac disease in patients with low serum IgA levels
TTG IgA antibodies are the recommended initial screening test for celiac disease in all age groups. Because these tests, and the earlier anti-gliadin IgA and anti-endomysial IgA (EMA) tests, were used clinically, it was quickly recognized that they may fail to detect celiac disease in those with IgA deficiency. Therefore, it is recommended that negative serum TTG IgA testing be followed by determination of total serum IgA.
In those with IgA deficiency, TTG IgG and EMA IgG appear to have similar sensitivity and specificity to TTG IgA-based tests in those with sufficient IgA. In particular, selective IgA deficiency (total serum IgA <0.07 g/L) is relatively rare compared to partial IgA deficiency (total serum IgA <2 SD below the mean for age). When we evaluated 1000 consecutive patients screened for celiac disease at our center, TTG IgA was highly sensitive (100%) in those with partial IgA deficiency. Similar findings have been reported in children.
FALLACY #4 – All individuals with celiac disease respond to a gluten-free diet
For many years, the importance of improving and increasing the diagnosis of celiac disease has been emphasized. Now, as the population with diagnosed celiac disease undergoing GFD expands, it is evident that many people with celiac disease do not respond to GFD. More than 15% of adults have persistent or frequent symptoms despite apparently strict GFD, also called “non-responsive celiac disease” (NRCD). 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 require very different management approaches, such as microscopic colitis, other food intolerances, small intestinal bacterial overgrowth. , and IBS.
Relatively few (0.04%-1.5%) have refractory celiac disease, defined as persistent symptoms and villous atrophy, despite a GFD. However, other conditions may still be associated with persistent villous atrophy, including occult gluten exposure, small intestinal bacterial overgrowth, autoimmune enteropathy, or common variable immunodeficiency. Other factors associated with symptomatic persistent villous atrophy include age over 70 years and use of proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or selective serotonin reuptake inhibitors.
Furthermore, mucosal recovery in a GFD is also not universal among those who respond clinically. In general, only 1/3 of adults have normal villous architecture (a healthy, healed intestine) after 2 years with a GFD and 2/3 after 5 years with a GFD. This is only based on evaluation of the duodenum, so the proportion of patients with celiac disease who achieve complete mucosal recovery of the entire small intestine is unknown. However, the rate of persistent villous atrophy decreases over time in GFD, so most people with celiac disease can eventually have mucosal recovery. Diagnosis during childhood and less severe histological damage at diagnosis have been associated with mucosal recovery.
FALLACY #5: The gluten-free diet is primarily used to treat celiac disease.
An increasing number of people are adopting a gluten-free or gluten-reduced diet for multiple reasons . Some experience relief from gastrointestinal or extraintestinal symptoms, either because they have non-celiac gluten sensitivity (NCGS) or IBS (often with fructan intolerance and non-intolerance to all gluten-containing grains). Others avoid gluten as part of a trend maintained by some athletes and public figures. In 2012 it was estimated that although at least 2 million people followed a general dietary diet in the United States, only 300,000 (15%) actually had celiac disease.
However, 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 is also increasing (from 0.1% in 2009-2010 to 0.1% in 2009-2010). .4% in 2013 –2014). However, in 2013-2014, there were still 0.28% with undiagnosed celiac disease, while at least 1.7% of the population avoided gluten without a celiac disease diagnosis .
FALLACY #6: Clinical response to a gluten-free diet (GFD) indicates the diagnosis of celiac disease
One consequence of the increased awareness of GFD is that self-treatment with a GFD before medical consultation is becoming more common. The serological and histological findings of celiac disease are normalized on a GFD, making subsequent diagnosis difficult. In addition, IBS and so-called non-celiac gluten sensitivity (NCGS) can respond to a GFD.
Differentiating between celiac disease and other conditions is clinically important because only celiac disease requires strict lifelong GFD, carries a risk of major health complications, and is associated with a risk of disease in children and other family members. By some definitions, an elevated IgA TTG excludes NCGS.
The conventional diagnostic protocol for NCGS includes following a regular gluten-containing diet for at least 6 weeks, followed by a gluten-free diet for at least 6 weeks. Responders should have a subsequent gluten test, preferably as a crossover with a placebo test. This methodology has identified some individuals with gluten sensitivity among populations with IBS and functional dyspepsia . Interestingly, in a recent randomized, double-blind, placebo-controlled, crossover study that included gluten, fructan, and placebo challenges, fructans were associated with significantly higher symptom scores than gluten in this patient population.
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 celiac disease odds ratio of 130 (95% CI 18.5–918.3). Those with celiac disease were also significantly more likely to have a nutrient deficiency, another autoimmune condition, or a family history of celiac disease.
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 family members are at risk. The negative predictive value of HLA-DQ2/DQ8 is very high (∼99%); however, the positive predictive value is much lower. Therefore, for the 40% of the population who carry HLADQ2 and/or DQ8, prolonged gluten challenge remains the clinical tool of choice to confirm (or exclude) celiac disease.
FALLACY #7: The gluten-free diet (GFD) has solved the problem of celiac disease
Despite 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 diet for the treatment of celiac disease was reported to be more burdensome than treatments for type 1 diabetes, irritable bowel syndrome, 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.
A strict GFD is difficult to maintain, particularly when eating food prepared by others outside the home, such as in restaurants or cafes, when traveling, or at social events. Groups that particularly struggle with a GFD include the elderly, the illiterate, those with mental or psychological impairments, and those with limited economic resources. Naturally gluten-free grains may have gluten-containing grains introduced during planting, harvesting, or processing. The details of food preparation are also important. Dusting meat with flour before grilling, using broth to cook rice, or steaming vegetables in pasta water are not described on menus. Gluten can also be found in some vitamins and supplements and non-consumer products, such as glue, lipstick, and play dough.
FALLACY #8: An "almost" gluten-free diet is adequate
Adhering to an absolutely strict 100% DLG is a tremendous challenge; For this reason, our patients often wonder if a less strict diet is enough. Catassi et al. attempted to answer this question in a double-blind micro-challenge study. Patients with biopsy-confirmed celiac disease who had normal duodenal villous architecture after being on strict GFD for 2 years or more were randomized to take 10 mg gluten, 50 mg gluten, or cornstarch placebo daily. day for 3 months while maintaining their usual strict GFD. The daily gluten exposure of 50 mg was a low dose equivalent to approximately one-fortieth of a slice of bread . The villous height crypt depth ratio (Vh:Cd) was similar in the 3 groups at the beginning of the study; however, there was a significant decrease in Vh:Cd in the 50 mg group after 3 months compared to placebo.
It is important to note that individual sensitivity is likely to be highly variable. One subject in the 10 mg group left the study after one month when he showed signs of relapse (vomiting, diarrhea, and bloating). The researchers included a trial period because some people participating in a research study may suddenly become stricter with their GFD, and this could bias the observed effects of the intervention; however, 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 into perspective the amount of gluten involved, a regular diet is around 5 to 15g of gluten/day in the Western world, which is at least 100 times the amount of gluten that is considered harmful.
A previous study among children compared the effects of a daily intake of 100 mg and 500 mg of gluten. Both groups had a worsening of Vh:Cd and IEL frequencies, except for one child in the 100 mg group who had a slight improvement in the Vh:Cd ratio. These studies are difficult to perform because they necessarily involve carried out on the basis of a "gluten-free" diet containing low levels of gluten. On the other hand, recent studies using urine and fecal gluten immunogenic peptide testing still detect gluten exposures among those with Marsh 0-1 histology. It is fair to conclude that individual responses to gluten exposure are highly variable, but chronic gluten exposure of at least 50 mg for more than a month will likely induce intestinal damage.
FALLACY #9: Most patients with known celiac disease follow a gluten-free diet (GFD)
In a survey of adults diagnosed with celiac disease in England, 40% reported intentional gluten exposure in the past 6 months and an additional 30% reported involuntary gluten exposure during the same period. Recently, our group completed the Determining Grams of Gluten Ingested and Excreted by Adults Eating Gluten-Free study. Eighteen adults with biopsy-confirmed celiac disease who had been on a gluten-free diet for 24 months collected food (25% portions in a “dog bag”), urine, and stool samples over a 10-day period. Although no intentional exposures to gluten were reported, two-thirds had at least one sample that tested positive for immunogenic gluten peptides. Eliminating all gluten in the diet can be an ambitious goal that is difficult to achieve even for highly motivated patients. This has been implicitly recognized for years because the definition of "gluten-free" is not absolute, but allows for 20 parts per million of gluten in foods.
FALLACY #10: A gluten-free diet (GFD) is a sufficient therapy for celiac disease
All guidelines for the management of celiac disease recommend lifelong adherence to a strict GFD. However, as mentioned above, the treatment burden is high in a GFD and it is an imperfect treatment for celiac disease. As such, this condition is ripe for drug development , as it is a commonly found disorder that requires lifelong therapy, with many steps in the pathogenesis of celiac disease being well elucidated.
Surveys suggest that most patients with celiac disease would be interested in medical therapy. Potential target populations for celiac disease have also evolved, with indications for therapies initially being as adjuncts to GFD. Our goal now is the ultimate goal: achieving “tolerance” to allow people with celiac disease to safely consume gluten, either in small amounts or ultimately in amounts found in a normal diet.
As with many other conditions, the diagnosis of celiac disease is limited by not remembering to include it as a diagnostic consideration. Failure to consider celiac disease remains a common factor in delays in diagnosis. Celiac disease has been reported on all continents except Antarctica, although epidemiological data are still lacking in several African and Asian countries. It occurs in overweight and obese people, and the effects of GFD on body habitus are variable.
Differentiating celiac disease from the NCGS is also crucial because the importance of strict compliance for patients with celiac disease is currently essential, but very burdensome. For many, symptoms persist, inadvertent exposures are common, and mucosal recovery is not universal. Inducing gluten tolerance 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.
