Broadly, my celiac patients suffer from two main problems. The first is poorly controlled celiac disease, with some combination of ongoing symptoms, enteropathy and laboratory abnormalities. This group, collectively referred to as nonresponsive celiac disease, is significant and although all current data on this issue comes from a few tertiary referral centers, it is likely that around a third of patients in North America would qualify as non-responsive.
Emerging data suggests that non-responsive celiac disease is not just limited to adults, but worryingly, frequently affects children as well. I have often argued in the past, and will do so in the future, that this is a large, unmet medical need, possibly one of the largest ‘untouched’ populations in gastroenterology. We also know that follow-up care in celiac disease is largely neglected and most patients and their physicians are unaware of their disease status.
All of this would seem to be a very good argument for routine repeat duodenal biopsy in celiac disease, were it not for the second major problem my patients endure, which is the burden and psychological impact of gluten avoidance. There is perhaps no disease where the burden of the disease itself is so closely balanced by the burden of the treatment. Indeed, unwillingness to adopt the gluten-free diet is one of the more commonly cited reasons why at-risk individuals choose not to get tested for celiac disease. Our goals for our celiac patients are identical to those with any other disorder, to enable individuals to live as full and normal lives as possible, and as with any disease, we as clinicians must carefully weigh the risks and benefits of treatment. With most other diseases, this entails a choice of treatment; an h2 blocker or a PPI, once a day or twice? Mesalamine, an immunomodulator, a biologic or a combination?
With celiac disease we have but one lonely choice, the gluten-free diet. We can ‘increase the dose’ through increasing restriction, going so far as the Gluten Contamination Elimination Diet, which prohibits eating of any processed food or food prepared outside of the home, and is associated with significant declines in social functioning and quality of life. Our other option is we can, to some extent, ‘decrease the dose’ by helping patients adapt to the gluten-free diet and make decisions which balance short- and long-term health risks of gluten exposure with quality of life and socialization.
For patients with celiac disease coming back to us with signs or symptoms of ongoing disease from GI symptoms to extraintestinal manifestation, such as progressive osteopenia, we should absolutely have a low threshold for repeat biopsy to assess disease status and optimize treatment as best we can with the limited tools available. On the other hand, routine follow-up biopsy is a very different animal. In this scenario, we would be bringing back patients for endoscopy who are clinically well, without significant symptoms or laboratory abnormalities. Certainly this would come with significant cost, but across medicine we commonly justify procedures and imaging for similarly uncertain costbenefit ratios. There would also be some risk, though esophagogastroduodenoscopy with biopsy is exceedingly safe for an invasive procedure.
Neither of these issues should be sufficient to outweigh the increasing data that persistent enteropathy (similar to chronic inflammation elsewhere in the body) is not a good thing and increases risk of osteoporosis, lymphoma and possibly overall mortality. Rather, I would argue that routine follow-up biopsy sends us hunting for something we currently we do not have any idea what to do with: asymptomatic persistent enteropathy.
Persistent enteropathy can have a number of etiologies. Ongoing gluten exposure is probably most common, but may also be related to slow healing, refractory celiac disease (not relevant for asymptomatic patients), secondary causes of inflammation, such as drugs or SIBO, and possibly, especially in older individuals, just the inability to fully heal after years or decades of undiagnosed and thus untreated celiac disease. Differentiating these conditions is challenging, and in some cases impossible. Even in the cases that we can attribute to gluten exposure, and doing so may become easier in the coming years with the development of diagnostic tests of stool and urine for gluten exposure, we do know whether asymptomatic persistent enteropathy is associated with poor long-term outcomes.
While data is convincing that on a population level, persistent enteropathy is associated with adverse outcomes, all of these studies are observational, with the minority of patients undergoing repeat endoscopy. This suggests that clinical concern prompted repeat endoscopy in many cases. Further, even if it was clear that asymptomatic persistent enteropathy is of clinical concern, there are legitimate reasons to doubt whether increased dietary admonishment can lead to sustained improvement in enteropathy and normalization of associated risks. Long-term dietary and behavioral change is difficult (if it were not, we would not be in the midst of an obesity epidemic), and lack of symptoms related to gluten exposure is a risk factor for poor long-term, gluten-free diet adherence. There is also a spectrum of gluten responsiveness in celiac disease and for some sensitive individuals there is no practical way to avoid the levels of gluten needed to trigger immune activation. Despite these issues, the impulse will be to treat all persistent enteropathy by ratcheting up the gluten-free diet, encouraging paranoia, putting strain on relationships and in extreme cases triggering development of orthorexia nervosa.
To be clear, the fact that a large proportion of the diagnosed celiac population has ongoing enteropathy for years after diagnosis is not acceptable. Concerted efforts are needed to develop both diagnostics which differentiate causes of persistent enteropathy, and behavioral and medical interventions which lead to mucosal healing. Until this work comes to fruition, we will not be ready to recommend routine repeat biopsy in celiac disease.
Dr. Leffler is an employee at Takeda Pharmaceuticals and has received honoraria and/or research support from Ferring, Actavis, Inova and Thermo-Fisher.