Celiac disease is diagnosed by small intestinal biopsy. As the popularity of the gluten-free diet has surged in the past decade, histology has largely remained intact as the arbiter between celiac disease and non-celiac gluten sensitivity, a condition whose etiology, pathogenesis and natural history remain incompletely understood. Though a pathway for a biopsy-free diagnosis of celiac disease has been proposed in select pediatric subpopulations, the biopsy has largely remained intact as the defining feature of celiac disease diagnosis. But there is less certainty about the role of the small intestinal biopsy in the follow-up of celiac disease after a patient has been diagnosed.
In the pre-serologic era, a second biopsy was central to the diagnostic process, since histologic recovery after starting a gluten-free diet was seen as a necessary component of proving the gluten’s causal role in the patient’s illness. But with the advent of celiac disease serologies, the clinicians now have biomarkers to follow. Celiac disease serologies usually decline to the normal range in response to strict adherence to the gluten-free diet, and a follow-up biopsy demonstrating healing is no longer necessary to prove that the patient has a gluten-sensitive enteropathy.
So what is the role of the follow-up biopsy after the diagnosis of celiac disease? I believe that that there are compelling reasons to offer this procedure, based on our emerging understanding of the role of villous healing and its correlation with adherence to the gluten-free diet and its prognostic implications (see Table 1).
“How am I doing?” was the calling card of Edward Koch when he was campaigning to be elected Mayor of New York City; it is also a question that our patients often ask in so many words. After the diagnosis of celiac disease and the institution of a gluten-free diet, there are several data points that are monitored. Symptoms usually improve within weeks, though approximately 20 percent of patients report persistent or recurrent symptoms. 1 Serologies typically normalize within six to 12 months of starting the gluten-free diet, though total normalization is not universal, and some patients have a persistent mild elevation of one or more celiac disease serologies that is of uncertain significance. Dietician assessment is essential upon diagnosis and often helpful when identifying areas of potential gluten exposure, but is reliant on patient recall and often-subjective parameters. Histologic recovery offers another important data point in assessing the effect of the only known therapy for celiac disease: the gluten-free diet.
An important principle in medicine is that a test should only be performed if its results would affect management decisions. The follow-up small intestinal biopsy, offered two to three years after initial diagnosis, passes muster on that front. A patient who has persistent symptoms despite attempting to adhere to a strict gluten-free diet may be suffering from those symptoms due to inadvertent gluten exposure, or due to a concurrent condition such as irritable bowel syndrome, pancreatic exocrine insufficiency, small intestinal bacterial overgrowth, additional food intolerances or microscopic colitis. The follow-up biopsy would provide important direction with regard to whether to focus on gluten exposure or to look for one of these other conditions.
Conversely, a patient who has clinical improvement may have uncertainty about whether his or her current dietary precautions are sufficient, or whether gluten exposure (and consequently intestinal damage) is still occurring. I have found the follow-up biopsy to be particularly useful in the scenario of an asymptomatic patient whose diagnosis of celiac disease was made based on screening due to a family history or associated condition (e.g. Type 1 diabetes). Such patients often have no “tell,” an acute adverse reaction to inadvertent gluten exposure, so the follow-up biopsy result would inform us regarding the adequacy of the patient’s current dietary practices. Analogous to inflammatory bowel disease, wherein treatment regimens are matched to inflammatory activity, the approach to avoiding gluten exposure — including precautions taken when eating out — can be modified in response to follow-up histology. Does healing matter? It has become increasingly apparent that the status of villous architecture on follow-up has prognostic importance. Though refractory celiac disease carries a guarded prognosis — particularly refractory celiac disease type 2, which can transform to enteropathy-associated T cell lymphoma — this condition is rare, occurring in less than 1 percent of patients with celiac disease. 2 A diagnosis of refractory celiac disease requires the presence of persistent symptoms of malabsorption and villous atrophy despite strict adherence to the gluten-free diet. Far more common are patients with persistent villous atrophy on follow-up biopsy who may or may not have some residual or intermittent symptoms. In the U.S., persistent villous atrophy was present on follow-up biopsy in 66 percent in one series of patients at two years after diagnosis. 3 This common scenario carries with it increased risk; a study of Swedish patients undergoing followup biopsy found that the increased risk of lymphoma that has been measured in celiac disease appears to be limited to those with persistent villous atrophy and that those with healing on follow-up biopsy do not have an increased risk of lymphoma compared to the general population.4
Follow-up biopsy can be incorporated into a management algorithm. Surveillance via duodenal biopsy appears to be a more sensitive marker of gluten exposure than serology, and patients with persistent villous atrophy can be targeted for additional dietary management under the care of a dietician skilled in the gluten-free diet.5The performance of a biopsy can therefore be an effective risk-stratifying tool for more intensive dietician guidance.
Advocating for this approach should be done with some humility. There are no randomized trials comparing routine follow-up biopsy to a no-follow-up biopsy approach, and we are left with evidence based on observational data. There are areas of uncertainty regarding the follow-up biopsy. Should the duodenal bulb be sampled (as this is now routinely done when diagnosing celiac disease) and what are the implications of persistent villous atrophy isolated to the bulb? Once a patient has been found to have normal villi, are any additional follow-up biopsies warranted in the years ahead? Is there any concern regarding patients whose villous height has normalized but who have persistent, increased intraepithelial lymphocytosis? Is such an outcome somehow inferior to total normalization? Finally, most of the data supporting the use of follow-up biopsy concerns adults and are not necessarily applicable to children (whose healing rates are higher, and for whom a follow-up endoscopy requires a greater degree of anesthesia).
While we await further studies to address these issues, the available evidence argues for offering a follow-up biopsy due to its potential to provide valuable, and actionable, information.
Dr. Lebwohl has no conflicts to disclose
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2. Ilus T, Kaukinen K, Virta LJ, et al. Refractory celiac disease in a country with a high prevalence of clinically diagnosed celiac. Aliment Pharmacol Ther 2014;39:418-25.
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4. Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and risk of lymphoproliferative malignancy in
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