Faculty Peer Reviewed
A 31-year-old woman presents to the clinic with chronic fatigue. She was diagnosed with iron deficiency anemia when she was 25 years old and has since taken oral contraceptives to limit bleeding during menstruation which she describes as minimal. She has a family history significant for an older brother with celiac disease. She is thin and her exam is significant for conjunctival pallor. Her laboratory findings are significant for a hemoglobin of 9.7 g/dL, a mean corpuscular volume of 72.3 fL, an iron level of 26 mcg/dL and a ferritin of 18 mcg/L.
How should the diagnosis of celiac disease be pursued as the possible etiology of her iron deficiency anemia?
Celiac disease is an immune disorder characterized by chronic inflammation of the gastrointestinal tract which can manifest clinically with diarrhea, abdominal discomfort and complications of malabsorption including weight loss, osteoporosis and iron deficiency anemia. These findings are classically seen, although they are neither sensitive nor specific for celiac disease.
Atypical presentations such as generalized fatigue are common, resulting in delays in diagnosis and misdiagnosis. For example, many patients ultimately found to have celiac disease are first diagnosed with irritable bowel syndrome.
In the last few decades, however, a greater understanding of the pathogenesis of celiac disease has led to the development of new tools to assist in detecting this disease. Along with these advances has come the recognition that celiac disease, once believed to be rare, has a prevalence of 1% in most populations and morbidity much greater than was originally appreciated when the disease was first described.
Celiac disease is a unique autoimmune syndrome in that the environmental antigen, gliadin, has been identified and treatment involves avoidance of that precipitant. Gliadin is a digested fragment of gluten, a storage protein present in wheat, barley and rye. In susceptible patients, the enzyme tissue transglutaminase (TTG) induces deamidation of gliadin peptides, initiating an inflammatory response mediated by gliadin-reactive CD4+ T-cells.
In 1997, Dieterich and colleagues identified TTG as the primary autoantigen in celiac disease. Elevated serum levels of IgA antibodies against TTG, as well as anti-endomysial antibody IgA, are directly correlated with celiac disease although their respective roles in disease pathogenesis are unknown.
Most guidelines for the diagnostic evaluation of a patient suspected to have celiac disease recommend serologic titers in conjunction with a small bowel biopsy. Biopsy typically shows blunting of the villa and endothelial lymphocytic infiltration. However, these findings are nonspecific and may be seen in other disease entities such as lactose intolerance, HIV and Crohn’s disease. For these reasons, the European Society for Pediatric Gastroenterology and Nutrition, in 2004, called for a non-invasive method for diagnosing celiac disease.
In contrast, Green and Cellier, in their 2007 review of celiac disease, wrote, “The diagnosis of celiac disease requires both a duodenal biopsy that shows the characteristic findings…and a positive response to a gluten-free diet.” In light of these shortcomings, there is no universally accepted algorithm for the diagnosis of celiac disease.
The high sensitivity and specificity of anti-EMA IgA (90% and close to 100%) and anti-TTG IgA (98% and 90%), has prompted outpatient providers to initiate investigation of celiac disease and more patients are being started on empiric gluten-restricted diets based solely on the results of blood tests. The wisdom of this practice is a topic of ongoing debate. Hadziselimovic and Burgin-Wolff reported that 99.8% of patients who test positive for the combination of anti-TTG IgA, anti-endomysial IgA and gliadin IgA and IgG antibodies have small bowel biopsies that show mucosal injury consistent with celiac disease. A related study found that 98% of patients with anti-TTG serum levels >100U ultimately had positive biopsy results.
These findings suggest that for patients in whom the clinical suspicion is high and serum titers are elevated, the empiric initiation of a gluten-free diet can be confidently recommended without a biopsy. The population of patients with intermediate serologic titers should be evaluated further with small bowel biopsies. Ultimately, a clinical response to the diet would confirm the diagnosis.
Furthermore, as antibody titers are directly correlated with the severity of disease, serologic markers can be used to monitor the response to therapy. A poor response to diet may necessitate endoscopic investigation to rule out processes associated with celiac disease like intestinal T-cell lymphoma and adenocarcinoma of the small intestine. In these patients, serologic testing provides no information about the state of the intestinal epithelium and these patients are often diagnosed when clinical symptoms persist despite adherence to a gluten-free diet.
A caveat to this approach is that even a very low incidence of false positivity would expose many patients to unnecessary dietary changes. As the American Gastroenterological Association technical guidelines point out, if one assumes a 1% prevalence in the general population, for the positive predictive value to be greater than 95%, the pre-test probability of a patient having celiac disease would have to be at least 35%. Considering the notoriously nonspecific presentations of celiac disease, this goal may be difficult to achieve.
In related studies, patients with mild celiac disease by histology had significantly decreased anti-TTG antibodies sensitivity and up to 60-70% of patients with celiac disease would not be identified by serologic screening with anti-TTG alone., These studies, however, included patients with a low suspicion of celiac disease and some argue that, in the correct population, judicious use of autoantibody testing would obviate the need for intestinal biopsy.
There is no gold standard for the diagnosis of celiac disease. The diagnosis is most confidently made with the support of a clinical picture consistent with celiac disease, elevated autoantibody levels, positive biopsy results and, ideally, an improvement with dietary changes. Perhaps, as serology testing improves, in a patient with a highly suspicious presentation and a positive antibody test, a trial of a gluten-free diet would offer only marginally less evidence as the same clinical findings with the additional support of a positive intestinal biopsy. Larger studies are needed to elucidate the feasibility of diagnosis based on serologic testing alone. For now, however, a multi-disciplinary approach to the diagnosis of this disease is recommended.
Dr. Cutler is a second year resident at NYU Langone Medical Center
Peer reviewed by Dr. Ilseung Cho, Division of Gastroenterology, NYU Langone Medical Center
Image of gluten-free cookies courtesy of Wikimedia Commons.
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