Melissa Snyder, Ph.D.
Associate Professor of Laboratory Medicine and Pathology
Division Chair, Clinical Biochemistry
Mayo Clinic, Rochester, Minnesota
Hello, everyone. My name is Melissa Snyder, and I am the co-director of the Antibody Immunology Laboratory at the Mayo Clinic in Rochester, Minnesota. I’m so glad you are able to join me for a brief review of published guidelines for the diagnosis of celiac disease, with a specific focus on the role of laboratory testing.
Before beginning the presentation, I will disclose that I have served as a member of the Strategic Advisory Committee for Werfen, which is an in vitro diagnostic company that manufactures and sells kits for celiac serology testing.
Celiac disease is caused by an inflammatory response by the patient’s own immune system, leading to damage of the small intestinal villi. The figure to the left shows a biopsy of a normal small intestine with intact villae. The middle and right-most figures represent the partial and total villous atrophy that can occur in celiac disease. Celiac disease develops in an individual having both the genetic susceptibility and the proper environmental exposure. The environmental exposure is dietary gluten, a cereal grain protein from wheat, barley, and rye. The genetic component are specific alleles of the human leukocyte antigen complex, namely HLA-DQ2 and HLA-DQ8.
The evaluation of a patient for suspected celiac disease includes a review of clinical symptoms and co-existing conditions; an intestinal biopsy with evidence of villous atrophy; serology testing for endomysial, tissue transglutaminase, and deamidated gliadin antibodies; and evaluation for the genetic risk factors including family history and presence of HLA-DQ2/DQ8.
Treatment for celiac disease is implementation of a gluten-free diet. The goal of this treatment is to remove the inciting antigen. With a successful gluten-free diet, the patient should begin to see resolution of their clinical symptoms, which is often accompanied by reconstitution of the intestinal villae and conversion to a negative serology. For a more in-depth review of diagnostic tests for celiac disease and the algorithms offered through Mayo Clinic Laboratories, I will refer you to the Hot Topic “Diagnostic Testing Algorithms for Celiac Disease.”
Since 2005, a number of diagnostic guidelines for celiac disease have been published by various professional organizations throughout the world. The guidelines are listed in this table in chronological order by publication date, although I want to point out that in 2020, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition published an update to their original paper, which was published in 2012. With the exception of the pediatric gastroenterology societies, all other guidelines focus primarily on adults, although most also highlight specific aspects of testing that would be relevant for children. Given the large number of published guidelines, it isn’t possible during this “Hot Topic” to review each in detail. Rather, I will focus on aspects of testing where there is general agreement across the various organizations, as well as instances where there is a lack of consensus. If you are interested in further details, the references for each guideline are included in this slide.
The first aspect of testing considered by all the guidelines is who should be tested. There is agreement that testing is indicated for certain symptomatic and asymptomatic persons. Symptomatic patients are those who have evidence of clinical symptoms that could be associated with celiac disease. In comparison, asymptomatic individuals would be those persons who have no appreciable clinical symptoms but are at higher risk for developing celiac disease in comparison to the general population.
In terms of symptoms, most guidelines consider both classical and nonclassical manifestations. These lists are not exhaustive, and there are subtle differences between the guidelines; however, most guidelines include diarrhea, weight loss, bloating, iron-deficient anemia, cachexia, and edema as classical symptoms, while nonclassical symptoms include abdominal pain and distension, constipation, vomiting, delayed puberty, amenorrhea, chronic fatigue, and hypertransaminasemia. Elevated liver enzymes is highlighted by several guidelines as one of the more common incidental lab findings which should prompt an evaluation for undiagnosed celiac disease.
Moving now to asymptomatic individuals, we find that most guidelines advocate for testing in first-degree relatives of patients with celiac disease and for patients who have been diagnosed with other autoimmune diseases, such as type I diabetes or autoimmune thyroid disease. Some guidelines also identify persons with selective IgA deficiency, as this phenotype occurs more frequently in patients with celiac disease compared to the general population. Lastly, individuals with certain chromosomal abnormalities, such as Down syndrome or Turner syndrome, should be considered for testing even in the absence of obvious clinical symptoms.
Next, we will look at what the guidelines suggest on how to test, and we will begin with serology. There is consensus that tissue transglutaminase IgA, or TTG-IgA, is the optimal initial test for the evaluation of suspected celiac disease. Most guidelines also highlight that TTG-IgA should be used in conjunction with total IgA to help identify cases of IgA deficiency and avoid false-negative celiac testing. For those individuals with low total IgA concentrations, TTG-IgG and deamidated gliadin IgG, either alone or in combination, are suggested. Endomysial antibodies, or EMA-IgA, is generally viewed as a good confirmatory test, particularly in patients with a low-titer TTG-IgA. Lastly, most guidelines recommend against using combinations of celiac-specific serologies, such as TTG-IgA and deamidated gliadin-IgG. The guidelines highlight that while this may result in a slight improvement in diagnostic sensitivity, the reduced specificity can become very problematic, especially in patients with low pre-test probability for celiac disease.
The next area to consider is HLA-DQ2 and DQ8 typing. Again, there is general agreement across the guidelines that HLA typing should not be used as part of the initial diagnostic evaluation for celiac disease and, in fact, is not needed to establish a diagnosis. However, there are some situations where HLA typing might be useful. For example, most guidelines recognize the value of HLA typing in patients who are on a gluten-free diet but in whom the diagnosis of celiac disease is uncertain. In this case, a gluten challenge would be considered for those individuals positive for either DQ2 or DQ8. In addition, most guidelines advocate for HLA typing in patients who have evidence of celiac disease on biopsy but negative serology testing. In these patients, the absence of HLA-DQ2 and DQ8 likely indicates an alternate diagnosis.
In contrast, use of HLA typing in asymptomatic, high-risk patients is more controversial. Some guidelines suggest it could be useful to exclude the diagnosis and thereby avoid lifelong monitoring for the disease. However, there is also recognition that the frequency of HLA-DQ2 and HLA-DQ8 is higher in certain risk groups, making a negative result less likely. In the end, there is consensus that the value of HLA typing lies with a negative result, which allows the clinician to exclude celiac disease as a diagnosis.
Lastly, we come to the most controversial point of celiac disease diagnostics, and this is the question of whether a biopsy is needed to make the diagnosis. I am showing the slide with the list of guidelines again because this question demonstrates clear differences between adult and pediatric groups.
To begin, let’s review the guidelines from the North American and European Societies for Pediatric Gastroenterology, Hepatology and Nutrition, and their recommendations on when a diagnosis of celiac disease can be established without a biopsy and when a biopsy is needed. In addition, for certain guidelines, we will need to distinguish between asymptomatic and symptomatic patients. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines published in 2005 are the most clear. These guidelines do not allow for a diagnosis of celiac disease without a biopsy and make it a requirement for any patient with a positive TTG-IgA or IgG.
The European Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines published in 2012 were the first to consider the “biopsy-free” diagnosis. For symptomatic patients, a positive TTG-IgA >10X the upper limit of normal with a positive EMA and HLA-DQ2/DQ8 typing has such a high predictive value for celiac disease that a biopsy would not be needed. In contrast, patients with a positive TTG-IgA <10X the upper limit of normal or a positive TTG-IgA >10X the upper limit of normal with a negative EMA should be further evaluated with a biopsy. For asymptomatic individuals, these guidelines recommended against diagnosis without a biopsy. For asymptomatic individuals, a positive TTG-IgA >3X the upper limit of normal or a positive TTG-IgA <3X the upper limit of normal with a positive EMA should be followed by a biopsy.
In 2020, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition published revised guidelines, which included significant changes compared to the original recommendations. First, there is no longer a differentiation between symptomatic and asymptomatic patients. Any individuals with a TTG-IgA >10X the upper limit of normal and a positive EMA could be diagnosed with celiac disease without a biopsy. In comparison, a positive TTG-IgA <10X the upper limit of normal or a positive TTG-IgA >10X the upper limit of normal with a negative EMA would require a biopsy. In addition, any positive celiac serology for the IgG isotype in an IgA-deficient individual should be confirmed with a biopsy.
So, with the increasing acceptance of a “no-biopsy” option for children, the question of whether this approach is possible for adults has been raised. Studies have shown that a positive TTG-IgA >10X the upper limit of normal with a positive EMA has very high predictive value in adults and could be relied upon to establish a diagnosis of celiac disease. However, all guidelines for celiac disease testing in adults still require a biopsy for diagnosis. One exception is from the World Gastroenterology Organization; this group suggests that serology and a response to a gluten-free diet may be used instead of a biopsy, which may be necessary in areas with limited endoscopy and pathology services.
While some guidelines acknowledge that a biopsy is probably not necessary to establish the diagnosis for every patient, there is recognition that a biopsy is important in adults for other reasons that are not as relevant in the pediatric population. In particular, a biopsy is critical for establishing the baseline, or pre-treatment, level of intestinal damage. This is important for patients who may have a limited response to treatment, where evaluation of ongoing disease activity might include serial biopsy and assessment of continued intestinal damage. The diagnostic biopsy might also provide information regarding current complications or the risk of developing complications in the future. Also, the diagnostic biopsy would help in the diagnosis of associated conditions, which are more common in adults, such as eosinophilic esophagitis or autoimmune gastritis.
In summary, the laboratory plays a significant role in the evaluation of patients with suspected celiac disease, although often this testing, and how to apply it to patient care, can be confusing. Multiple diagnostic guidelines for celiac disease have been published over the last 15 years, covering both adult and pediatric populations. There is good consensus across the guidelines in terms of who to test, the role of serology, and the application of genetic testing. The most controversial aspect with celiac disease diagnostics is whether a biopsy can be avoided in certain individuals, the so-called “no biopsy” diagnosis. While this appears to be a viable and attractive option in children, a biopsy continues to be relevant for adults, providing both diagnostic and prognostic information.
I hope this presentation has provided you with useful information regarding diagnostic guidelines for celiac disease. Thank you for your participation.
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